Highly Active Antiretroviral Treatment Era Research Articles

The dual protease inhibitor lopinavir/ritonavir (LPV/r) exerts genotoxic stress on lung cells

The Sub-Saharan countries, particularly South Africa has the largest number of people living with HIV, accompanied by the largest antiretroviral treatment (ART) programme in the world. The Highly Active Antiretroviral Treatment (HAART) is the most effective regimen against HIV/AIDS and has improved the lifespan and quality of life of HIV positive patients. HAART has also led to a decrease in the incidence of AIDS defining cancers (ADCs) while there is an increased incidence of the non-AIDS Defining Cancers (NADCs), such as lung cancer in the HAART era. The association between lung tumourigenesis and the use of HAART components such as the dual protease inhibitor (PI) lopinavir/ritonavir (LPV/r) is poorly understood. Using cell and molecular biological approaches, this study aimed at elucidating the effects of LPV/r on the regulation of the cell cycle related genes in normal (MRC-5) and adenocarcinoma (A549) lung cells. Initially, the nuclear integrity of these cells in response to LPV/r was determined using DAPI staining. The effect of LPV/r on cell cycle genes was evaluated through the use of a RT2 PCR gene array of 84 genes related to the cell cycle signaling pathway. The PCR array data was validated by Real-Time Quantification PCR (RT-qPCR). Ingenuity Pathway Analysis (IPA) bio-informatics tool was employed to disclose the molecular mechanism/s observed at cellular and gene expression levels. Loss of nuclear integrity and the upregulation of the p53 DNA damage response (DDR) pathway was revealed by DAPI staining, differential gene expression and IPA core analysis. Furthermore, MAD2L2 and AURKB which also play a role in the DDR pathway were shown to be differentially expressed. The activation of the CASP3 gene in response to LPV/r in A549 cells was also observed. The findings of this study suggest genotoxic properties of LPV/r in healthy normal lung fibroblasts cells and anti-tumour properties in the A549 cells.

Cotransmission of Malaria and HIV to Infants of Mothers Coinfected With Malaria and HIV in the HAART Era in Benin City, Nigeria.

Malaria and HIV are vertically transmitted to infants. In an era where specific interventions are available to reduce the burden of malaria in pregnancy and vertical transmission of HIV, we examined the transmission and cotransmission of HIV and malaria to infants of mothers coinfected with malaria and HIV. A cross-sectional analytic study performed on 101 HIV/malaria-coinfected mothers and their infants for whom DNA polymerase chain reaction results were available. Blood film for malaria parasites was performed on cord blood and peripheral blood on days 1, 3, and 7 in the newborns. Maternal peripheral blood film for malaria parasite was performed at delivery, and placental tissue was obtained for confirmation of placental malaria by histology. All infants received DNA polymerase chain reaction testing for HIV at 6-8 weeks of life. Cotransmission of malaria and HIV occurred in 2 (1.98%) infants. Vertical transmission of HIV occurred in 7 (7%) babies, whereas congenital malaria was present in 32 (31.7%) babies. The transmission of HIV and presence of congenital malaria were not significantly associated with each other P = 1.000. Of the 88 babies of mothers who commenced highly active antiretroviral treatment (HAART) before pregnancy, 5 (5.7^) had HIV, which was significantly less than 2 (40%) of 5 babies of mothers who commenced HAART during pregnancy P = 0.04. Among mothers coinfected with malaria and HIV, vertical transmission of malaria and HIV was not associated with each other. HAART reduces vertical transmission of HIV especially if started before pregnancy.

LINFOMA PRIMARIO DEL SISTEMA NERVIOSO CENTRAL COMO PRIMERA MANIFESTACIÓN DE SIDA. PRESENTACIÓN DE UN CASO Y REVISIÓN DE LA LITERATURA

El linfoma primario del sistema nervioso central (LPSNC) es una neoplasia infrecuente que comprende solo el 5% del total de los linfomas de localización extranodal. El LPSNC se define como un linfoma de tipo No Hodgkin (LNH) que solo infiltra el eje cerebro espinal sin compromiso sistémico. Esta neoplasia es más frecuente en sujetos con inmunodeficiencias congénitas y adquiridas. En los pacientes con SIDA, el LPSNC ocurre con igual incidencia en todos los grupos de riesgo y edades pero con una mayor prevalencia en aquellos con recuentos de linfocitos T CD4 + de < de 50 células/µL. Se trata de un linfoma de células grandes, de alto grado de malignidad, y fuertemente asociado en su patogenia al virus de Epstein Barr (VEB) cuyo genoma se detecta en las células linfoides atípicas. La presencia del genoma del VEB se detecta en el 100% de los casos de LPSNC asociado al SIDA pero esto no ocurre en otras clases de pacientes con esta misma neoplasia. En pacientes con SIDA y lesiones de masa cerebral ocupante, la detección del genoma del VEB en el líquido cefalorraquídeo (LCR) a través de la reacción en cadena de la polimerasa (PCR) tiene una sensibilidad del 83% a 100% y una especificidad > del 90% para el diagnóstico. El uso difundido de la terapia antirretroviral de gran actividad (TARGA) se asoció con una declinación en la incidencia de LPSNC. El pronóstico de esta neoplasia en pacientes con SIDA es pobre y se asocia con una mediana de supervivencia de 2 a 3 meses en la era previa a la TARGA con una discreta prolongación en la supervivencia con la TARGA. Se presenta un paciente que desarrolló un LPSNC como primera manifestación de SIDA y se efectúa una actualización de la literatura sobre el tema.

Epidemiology and long-term survival in HIV-infected patients with Pneumocystis jirovecii pneumonia in the HAART era: experience in a university hospital and review of the literature.

As highly active antiretroviral treatment (HAART) is widely available, the incidence of Pneumocystis jirovecii pneumonia (PJP) has decreased significantly but still represents a significant cause of morbidity and mortality in developed countries.We analyzed all the cases with PJP in human immunodeficiency virus (HIV)-infected patients from 2000 to 2013 in a university hospital in Barcelona, Spain, and conducted a systematic literature review to evaluate data regarding incidence, mortality, and long-term survival after PJP in developed settings.One hundred thirty-six episodes of PJP were analyzed. During the study period, the incidence decreased significantly (from 13.4 cases/1000 patients-year to 3.3 cases/1000 patients-year, P < 0.001). Oppositely, median age of the patients increased from 34 years in 2000 to 45 in 2013 (P = 0.024). PJP preceded HIV diagnosis in nearly 50% of the cases. Fifteen (11%) patients died during the PJP episode. The main risk factor for in-hospital mortality in our cohort was age >50 years (odds ratio 4.96, 95% confidence interval [CI] 1.45–15.14). Patients who survived were followed-up during a mean time of 44 months. Overall 5-year survival of patients after hospital discharge was 73%. Survival likelihood was 54% higher (88% [95% CI 81–96]) among HAART-adherent patients.Mean age and the proportion of patients with unknown HIV infection at the time of PJP diagnosis have increased in developed countries in the HAART era. Although the incidence has decreased, in-hospital mortality remains stable in this setting. Long-term survival is very high among HAART-adherent patients.

Clinical features and laboratory findings of human parvovirus B19 in human immunodeficiency virus-infected patients

Immunocompromised patients may develop severe chronic anaemia when infected by human parvovirus B19 (B19V). However, this is not the case in human immunodeficiency virus (HIV)-infected patients with good adherence to highly active antiretroviral treatment (HAART). In this study, we investigated the clinical evolution of five HIV-infected patients receiving HAART who had B19V infections confirmed by serum polymerase chain reaction. Four of the patients were infected with genotype 1a strains and the remaining patient was infected with a genotype 3b strain. Anaemia was detected in three of the patients, but all patients recovered without requiring immunoglobulin and/or blood transfusions. In all cases, the attending physicians did not suspect the B19V infections. There was no apparent relationship between the infecting genotype and the clinical course. In the HAART era, B19V infections in HIV-positive patients may be limited, subtle or unapparent.

Pediatric Human Immunodeficiency Virus infection and cancer in the Highly Active Antiretroviral Treatment (HAART) era

Highly active antiretroviral therapy (HAART) changed the natural history of pediatric HIV infection. This review focuses on trends of HIV-associated cancers in childhood in the HAART era and analyses potential pathogenetic mechanisms. HAART reduced AIDS-defined-malignancies (ADM), but incidence of several non-ADM is increasing. HIV-associated immune activation and inflammation, promoting tumorigenesis, can only partially be reduced by HAART. In addition, HIV-infected children may undergo accelerated immune senescence that favors cancer development. How HAART affects this condition is an open question. Lastly, there is no evidence that prenatal exposure to HAART increases the risk of cancer in childhood, but long-term studies are needed.

Challenges, Coping Strategies, and Recommendations Related to the HIV Services Field in the HAART Era: A Systematic Literature Review of Qualitative Studies from the United States and Canada

Qualitative research methods have been utilized to study the nature of work in the HIV services field. Yet current literature lacks a Highly Active Anti-Retroviral Treatment (HAART) era compendium of qualitative research studying challenges and coping strategies in the field. This study systematically reviewed challenges and coping strategies that qualitative researchers observed in the HIV services field during the HAART era, and their recommendations to organizations. Four online databases were searched for peer-reviewed research that utilized qualitative methods, were published from January 1998 to February 2012, utilized samples of individuals in the HIV services field; occurred in the U.S. or Canada, and contained information related to challenges and/or coping strategies. Abstracts were identified (n=846) and independently read and coded for inclusion by at least two of the four first authors. Identified articles (n=26) were independently read by at least two of the four first authors who recorded the study methodology, participant demographics, challenges and coping strategies, and recommendations. A number of challenges affecting those in the HIV services field were noted, particularly interpersonal and organizational issues. Coping strategies were problem- and emotion-focused. Summarized research recommendations called for increased support, capacity-building, and structural changes. Future research on challenges and coping strategies must provide up-to-date information to the HIV services field while creating, implementing, and evaluating interventions to manage current challenges and reduce the risk of burnout.

Long‐term follow‐up of patients with HIV‐related diffuse large B‐cell lymphomas treated in a phase II study with rituximab and CHOP

Long‐term follow‐up of patients with <scp>HIV</scp>‐related diffuse large <scp>B</scp>‐cell lymphomas treated in a phase <scp>II</scp> study with rituximab and <scp>CHOP</scp>

Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women.

Despite the use of highly active anti-retroviral treatment (HAART), cognitive impairment remains prevalent in HIV. Indeed a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. Neurology 74(16):1260-1266 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. The participants were members of the Women's Interagency HIV Study. In the analysis of cross-sectional data using general linear models, we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models, significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI 3.5 to 17.5, p = 0.003, N = 1,130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1,130). The summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.

AIDS Morbidity and Mortality in Brazilian Children Before and After Highly Active Antiretroviral Treatment Implementation

The objective of this study was to analyze regional trends over time of acquired immunodeficiency syndrome (AIDS) cases and deaths in Brazilian children, before and after implementation of free access to highly active antiretroviral treatment (HAART). We performed a nation-wide study with an ecologic design and a time-series analysis of AIDS incidence and mortality rates in children (0-12 years of age), using polynomial regression models. Data were obtained from official national databases on age group, residence region, and year of AIDS diagnosis and death (1984-2008). Between 1984 and 2008, 14,314 (2.7%) AIDS cases and 5041 deaths (2.3% of all AIDS-related deaths) were reported in Brazilian children. Incidence after 1996 was reduced by 23%, as compared with the pre-HAART era. The mortality rate observed in the HAART era was reduced by 63.6%. There was a significant reduction in the incidence in the Southeast and Central-West regions (P < 0.001), but the less industrialized North region showed an increase in the pre-HAART era (P < 0.001), and the Northeast region showed a stabilization trend (P < 0.001). In the South region, the incidence of AIDS increased in the 0 to 4 years subgroup. A reduction of AIDS mortality in the Southeast (P < 0.001), South, and Central-West regions (P < 0.001) was seen, but the Northeast and North regions maintained an increasing mortality trend (P < 0.001). Despite the overall reduction in AIDS-related cases and deaths among children in Brazil since HAART, marked regional differences continue to exist. These reflect structural factors, different transmission dynamics, and operational issues. There is a need for improving the health service network with special emphasis on the less developed regions.

Mortality among HIV/AIDS in-patients on admission in a tertiary hospital in Nigeria

Background: HIV/AIDS is one of the leading causes of morbidity and mortality in Nigeria and the disease has led to a sharp increase in the admission rate in many hospitals especially those offering care to those infected. The emergence of Highly active antiretroviral treatment (HAART) has also reduced the risk of mortality in patients diagnosed with HIV/AIDS, who are adherent to therapy. The University of Benin Teaching Hospital (UBTH) is a tertiary centre which is also a treatment centre catering for over 7000 People Living with HIV/AIDS (PLWA). Objective: To determine the mortality rate and causes of death of admitted patients with HIV/AIDS at UBTH in the HAART era. Methodology: The study was carried out over a one year period from January 2003-December 2004 .All patients admitted to the medical wards of the University of Benin Teaching Hospital with a confirmed diagnosis of HIV/AIDS aged 15 years and above were admitted in the study. Data analysis was done using frequency tables, means and proportions.ResultsOf the 174 patients admitted in the wards with a confirmed diagnosis of HIV/AIDS during the study period, 49 died, giving a crude death rate of 28.2 %. The male to female ratio was 1.9:1. The age group most affected was the 30-39 age group both in males and females. The highest cause of death was AIDS (18.4%) followed by severe anaemia (12.2%).Others include gastroenteritis (8.2%) pulmonary tuberculosis with anemia,(8.2%),CNS Toxoplasmosis (8.2%). The major factors leading to these deaths were late presentation to hospital, poor adherence to therapy and financial insolvency.More effort needs to be directed at voluntary counseling and testing, public enlightenment to facilitate prevention and early presentation, and adherence counseling for those on treatment. These will reduce the high mortality rate in the HAART era.Keywords: Mortality, Human immunodeficiency virus, Benin City.

Modelling the relationship between antiretroviral treatment and HIV prevention: limitations of the Spectrum AIDS Impact Model in a changing policy environment

This paper shows how two publicly available epidemiological modelling packages, namely the Spectrum AIDS Impact Model and the ASSA2003 AIDS and Demographic Model, predict very different impacts from rolling out highly active antiretroviral treatment (HAART) on new HIV infections. Using South Africa as a case study, it shows that the ASSA2003 model predicts a significant drop in new HIV infections as HAART is rolled out, whereas the Spectrum model assumes that HAART does not have a preventative impact (and in fact generates a small increase in new HIV infections). Users will thus draw different conclusions about the public health benefits of HAART depending on which modelling package they use. Despite being presented as a policy-oriented modelling tool capable of exploring 'what if' questions about the impact of different policy choices, the Spectrum model is illequipped to do so with regard to a HAART rollout. Unlike Spectrum, ASSA2003 is more flexible and its assumptions are clear. Better modelling and more information (including about the relationship between HAART and sexual risk behaviour) is required to develop appropriate public-policy modelling for the HAART era.

Risk Factors for Opportunistic Illnesses in Children With Human Immunodeficiency Virus in the Era of Highly Active Antiretroviral Therapy

To examine the relationship between the use of highly active antiretroviral treatment (HAART) and the occurrence of opportunistic illnesses (OIs) among children perinatally infected with human immunodeficiency virus. Prospective cohort study. Pediatric AIDS Clinical Trials Group 219C cohort. From September 15, 2000, to August 31, 2003, 1927 children perinatally infected with human immunodeficiency virus and receiving HAART were followed up. Main Exposures Age at initiating HAART, duration of HAART use, CD4+ T-lymphocyte percentage, and human immunodeficiency virus 1 viral load. Incidence rates for Centers for Disease Control and Prevention OI category B and OI category C events were calculated. The association between main exposures and OI occurrence was estimated using proportional hazards regression. Of 1927 subjects, 226 (12.7%) developed OIs during follow-up. Incidence rates were 4.99 per 100 person-years (95% confidence interval, 4.30-5.76) for first OI category B events and 1.47 per 100 person-years (95% confidence interval, 1.12-1.91) for first OI category C events. Duration of HAART use was not related to OI risk. Older age (age >10 years) at HAART initiation was associated with increased risk of a first OI (hazard ratio, 2.48; 95% confidence interval, 1.23-5.00) compared with initiating HAART in children younger than 2 years. This increased risk diminished after adjusting for CD4+ T-lymphocyte percentage and Centers for Disease Control and Prevention disease category at HAART initiation. More children with OIs than without OIs had a CD4+ T-lymphocyte percentage of less than 15% at HAART initiation (49.6% of children with OIs vs 23.7% of children without OIs), at enrollment (41.2% of children with OIs vs 7.7% of children without OIs), and at the end of follow-up (41.2% of children with OIs vs 8.3% of children without OIs). Opportunistic illnesses are occurring in the pediatric human immunodeficiency virus population in the HAART era, mainly in children with persistently low CD4+ T-lymphocyte percentages. Lack of a sustained response to HAART rather than age at or duration of HAART use is predictive of OI risk.

Risk factors and causes of death in the Australian HIV Observational Database

Mortality rates in HIV-infected people remain high in the era of highly active antiretroviral treatment (HAART). The objective of this paper was to examine causes of deaths in the Australian HIV Observational Database (AHOD) and compare risk factors for HIV-related and HIV-unrelated deaths. Data from AHOD, an observational study of people with HIV attending medical sites between 1999 and 2004, were analysed. Primary and underlying causes of death were ascertained by sites completing a standardised cause of death form. Causes of death were then coded as HIV-related or HIV-unrelated. Risk factors for HIV-related and unrelated deaths were assessed using survival analysis among patients who had a baseline and at least one follow-up CD4 and RNA measure. The AHOD had enrolled 2329 patients between 1999 and 2004. During this time, a total of 105 patients died, with a crude mortality rate of 1.58 per 100 person years. Forty-two (40%) deaths were HIV-related (directly attributable to an AIDS event), 55 (52%) HIV-unrelated (all other causes), and eight had unknown cause of death. Independent risk factors for HIV-related deaths were low CD4 count and receipt of a larger number of antiretroviral treatment combinations. Among HIV-unrelated deaths, low CD4 count and older age were independent risk factors. In AHOD in the HAART era, mortality in people with HIV remains around 10-fold higher than in the general population. In our analyses, HIV-unrelated deaths were associated with more advanced HIV disease in a similar way to HIV-related deaths.

A Population-Based Analysis of Temporal Trends in the Incidence of Squamous Anal Canal Cancer in Relation to the HIV Epidemic

Squamous cell carcinoma of the anal canal (SCCA) is etiologically linked to human papillomavirus, and its incidence is increased among the immunosuppressed. We used data from the Surveillance, Epidemiology, and End Results program to analyze the incidence of SCCA in relation to 3 separate periods during the HIV epidemic: the pre-HIV era (1973-1981), the HIV era (1982-1995), and the highly active antiretroviral treatment (HAART) era (1996-2001). The incidence per 100,000 population of SCCA increased from 0.6 in the pre-HIV era to 0.8 in the HIV era and to 1.0 in the HAART era. The gap in SCCA incidence between women and men decreased from a ratio of 1.6:1 in the pre-HIV era to 1.5:1 in the HIV era and to 1.2:1 in the HAART era. There was a significant increase in incidence rates among men and women aged 30 to 54 years in the HAART era compared with the HIV era. Men were more likely to be diagnosed with early-stage disease, but they were less likely than women to receive radiation therapy. The incidence of SCCA has particularly increased among men and those between 30 and 54 years of age since the introduction of HAART.

The changing pattern of HIV neuropathology in the HAART era.

Highly active antiretroviral treatment (HAART), which has been available for most AIDS patients in France since 1996, has resulted in a dramatic improvement of the progression of the disease. From the survey of our series of 343 brains with acquired immunodeficiency syndrome (AIDS) from patients who died between 1985 and 2002, we found both quantitative and qualitative changes in the pattern of human immunodeficiency virus (HIV) neuropathology. Quantitatively, despite a dramatic decrease in the number of autopsies, brain involvement remained a major cause of death. There was an overall decrease in incidence of cerebral toxoplasmosis, cytomegalovirus encephalitis (CMVE), and HIV encephalitis (HIVE), for which successful treatment is available. This contrasted with the unchanged incidence of progressive multifocal leukoencephalopathy (PML) and malignant non-Hodgkin lymphomas (MNHL). However, when looking closer at the 3 last years, the incidence of diseases affecting patients with severe immunodepression (CMVE, PML, and MNHL) decreased between 2000 and 2002, whereas infections occurring in patients with milder immunodeficiency, toxoplasmosis, varicella-zoster encephalitis (VZVE), or herpes simplex virus encephalitis (HSVE) became more frequent. In addition, we found uncommon types of brain infection such as BK virus encephalitis or general paresis. Finally, we described new variants of HIVE: severe leukoencephalopathy with intense perivascular macrophage and lymphocyte infiltration, possibly due to an exaggerated response from a newly reconstituted immune system, and chronic "burnt out" forms of HIVE as VZVE, toxoplasmosis, or PML, possibly associated with prolonged survival, in which neither inflammation nor organisms could be detected. These findings are compared with those reported in other neuropathological studies from different developed countries.