Switch to etravirine for HIV-positive patients receiving statin treatment: a prospective study

BACKGROUND Life style changes and statins are the cornerstones in management of dyslipidemia in HIV-infected patients. Replacement of an antiretroviral therapy (ART) component is a proposed therapeutic strategy to reduce cardiovascular risk. In dyslipidemic HIV-positive patients, we assessed the efficacy of replacing boosted protease inhibitor (bPI) or efavirenz (EFV) by etravirine (ETR) as an alternative to statin therapy. MATERIALS AND METHODS A prospective, open-label, multicentre, 12-week study of HIV-infected patients on ART including bPI or EFV, and statin treatment. Four weeks after statin interruption, bPI or EFV were switched to ETR (400 mg, 8 weeks) if serum low-density lipoprotein cholesterol (LDL-c) was ≥ 3 mmol/L. The primary endpoint was the proportion of patients on ETR with no indication for statin treatment at study completion. Serum levels of HIV-RNA, lipids, and biomarkers of cardiovascular disease were also measured. (ClinicalTrialsgov: NCT01543035). RESULTS The 31 included patients had a HIV1-RNA <50 copies/mL (median age, 52 years; median CD4, 709 cell/mL; median LDL-c, 2.89 mmol/L), 68% were on EFV, 32% on bPI. At week 4, 27 patients switched to ETR. At study completion, 15 patients (56%) on ETR did not qualify for statin treatment. After the ETR switch, serum levels of the cardiovascular biomarkers sICAM and MCP1/CCL2 decreased by 11.2% and 18.9%, respectively, and those of CCL5/RANTES and tissue inhibitor of metalloproteinase-1 increased by 14.3% and 13.4%, respectively, indicating reduced cardiovascular risk. There were no notable treatment-related adverse events. CONCLUSIONS Replacing bPI or EFV by ETR is a viable strategy to obviate primary prevention statin treatment. This article is protected by copyright. All rights reserved.

Growth in Virologically Suppressed HIV Positive Children on Antiretroviral Therapy: Individual and Population-Level References

BACKGROUND Combination antiretroviral therapy (ART) suppresses viral replication in HIV-infected children. The growth of virologically suppressed children on ART has not been well documented. We aimed to develop dynamic reference curves for weight-for-age z scores (WAZ) and height-for-age z scores (HAZ). RESULTS A total of 4,876 children were followed for 7,407 person-years. Analyses were stratified by baseline z-scores and age, which were the most important predictors of growth response. The youngest children showed the most pronounced increase in weight and height initially but catch-up growth stagnated after 1-2 years. Three years after starting ART, WAZ ranged from -2.2 (95% Prediction interval -5.6 to 0.8) in children with baseline age "5 years and z-score "-3 to 0.0 (-2.7 to 2.4) in children with baseline age "2 years and WAZ "-1. For HAZ the corresponding range was -2.3 (-4.9 to 0.3) in children with baseline age"5 years and z-score "-3 to 0.3 (-3.1 to 3.4) in children with baseline age 2-5 years and HAZ "-1. CONCLUSIONS We have developed an online tool to calculate reference trajectories in fully suppressed children. The web application could help to define 'optimal' growth response and identify children with treatment failure.

Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study.

BACKGROUND Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL. METHODS We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55 826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders. FINDINGS Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9). INTERPRETATION The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING National Institutes of Health.

Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons.

BACKGROUND The European AIDS Clinical Society (EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. GUIDELINE HIGHLIGHTS The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment (START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (PrEP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug-drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus (HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. CONCLUSIONS The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview.

Incidence of AIDS-Defining and Other Cancers in HIV-Positive Children in South Africa: Record Linkage Study.

BACKGROUND Little is known on the risk of cancer in HIV-positive children in sub-Saharan Africa. We examined incidence and risk factors of AIDS-defining and other cancers in pediatric antiretroviral therapy (ART) programs in South Africa. METHODS We linked the records of five ART programs in Johannesburg and Cape Town to those of pediatric oncology units, based on name and surname, date of birth, folder and civil identification numbers. We calculated incidence rates and obtained hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression models including ART, sex, age, and degree of immunodeficiency. Missing CD4 counts and CD4% were multiply imputed. Immunodeficiency was defined according to World Health Organization 2005 criteria. RESULTS Data of 11,707 HIV-positive children were included in the analysis. During 29,348 person-years of follow-up 24 cancers were diagnosed, for an incidence rate of 82 per 100,000 person-years (95% CI 55-122). The most frequent cancers were Kaposi Sarcoma (34 per 100,000 person-years) and Non Hodgkin Lymphoma (31 per 100,000 person-years). The incidence of non AIDS-defining malignancies was 17 per 100,000. The risk of developing cancer was lower on ART (HR 0.29, 95%CI 0.09-0.86), and increased with age at enrolment (>10 versus <3 years: HR 7.3, 95% CI 2.2-24.6) and immunodeficiency at enrolment (advanced/severe versus no/mild: HR 3.5, 95%CI 1.1-12.0). The HR for the effect of ART from complete case analysis was similar but ceased to be statistically significant (p=0.078). CONCLUSIONS Early HIV diagnosis and linkage to care, with start of ART before advanced immunodeficiency develops, may substantially reduce the burden of cancer in HIV-positive children in South Africa and elsewhere.

Retention in care during the first 3 years of antiretroviral therapy for women in Malawi's option B+ programme: an observational cohort study

Background Studies of Malawi's option B+ programme for HIV-positive pregnant and breastfeeding women have reported high loss to follow-up during pregnancy and at the start of antiretroviral therapy (ART), but few data exist about retention during breastfeeding and after weaning. We examined loss to follow-up and retention in care in patients in the option B+ programme during their first 3 years on ART. Methods We analysed two data sources: aggregated facility-level data about patients in option B+ who started ART between Oct 1, 2011, and June 30, 2012, at 546 health facilities; and patient-level data from 20 large facilities with electronic medical record system for HIV-positive women who started ART between Sept 1, 2011, and Dec 31, 2013, under option B+ or because they had WHO clinical stages 3 or 4 disease or had CD4 counts of less than 350 cells per μL. We used facility-level data to calculate representative estimates of retention and loss to follow-up. We used patient-level data to study temporal trends in retention, timing of loss to follow-up, and predictors of no follow-up and loss to follow-up. We defined patients who were more than 60 days late for their first follow-up visit as having no follow-up and patients who were more than 60 days late for a subsequent visit as being lost to follow-up. We calculated proportions and cumulative probabilities of patients who had died, stopped ART, had no follow-up, were lost to follow-up, or were retained alive on ART for 36 months. We calculated odds ratios and hazard ratios to examine predictors of no follow-up and loss to follow-up. Findings Analysis of facility-level data about patients in option B+ who had not transferred to a different facility showed retention in care to be 76·8% (20 475 of 26 658 patients) after 12 months, 70·8% (18 306 of 25 849 patients) after 24 months, and 69·7% (17 787 of 25 535 patients) after 36 months. Patient-level data included 29 145 patients. 14 630 (50·2%) began treatment under option B+. Patients in option B+ had a higher risk of having no follow-up and, for the first 2 years of ART, higher risk of loss to follow-up than did patients who started ART because they had CD4 counts less than 350 cells per μL or WHO clinical stage 3 or 4 disease. Risk of loss to follow-up during the third year was low and similar for patients retained for 2 years. Retention rates did not change as the option B+ programme matured. Interpretation Our data suggest that pregnant and breastfeeding women who start ART immediately after they are diagnosed with HIV can be retained on ART through the option B+ programme, even after many have stopped breastfeeding. Interventions might be needed to improve retention in the first year on ART in option B+. Funding Bill & Melinda Gates Foundation, Partnerships for Enhanced Engagement in Research Health, and National Institute of Allergy and Infectious Diseases.

When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.

OBJECTIVE To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). DESIGN Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. METHODS Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. RESULTS In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. CONCLUSIONS Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Antiretroviral therapy adherence and the use of condoms among African American HIV-positive crack cocaine users

Safer sex practices, such as consistent condom use, are essential to reduce HIV transmission. Determining causes and/or co-variants related to the likelihood of participating in high-risk sexual behaviors may allow the content of interventions and treatments to minimize HIV transmission to be tailored more effectively. The goal of this study was to examine whether a relationship exists between consistent condom use among African American HIV-positive crack cocaine users and both (1) the use of antiretroviral therapy, and (2) adherence to antiretroviral therapy regimens. The study population consisted of 390 participants. They were at least 18 years old, African American, HIV-positive, and had used crack cocaine within a month prior to an interview conducted sometime between April, 2004, and September, 2007. Bivariate associations were examined using contingency tables and χ2-statistics. The Mantel-Haenszel method was used to control for confounding. This study found neither a significant relationship between use of antiretroviral therapy and consistent condom use (Odds ratio (OR) = 1.38; 95% Confidence interval (95%CI) = 0.86–2.22), nor an association between antiretroviral therapy adherence and consistent condom use (OR = 1.02, 95%CI = 0.60–1.75). The exception was more consistent condom use when sex was traded for money or drugs in those on antiretroviral therapy, compared to those not on such therapy (OR = 2.28, 95%CI = 1.08–4.85). Further studies examining condom use and HIV treatment adherence are recommended. ^

The care to share HIV disclosure study - the attitudes toward and beliefs about HIV disclosure among perinatally-infected HIV-positive youth and their caregivers

HIV incidence has not changed since the introduction of the pandemic. Daily 14,000 persons are infected with HIV and 25 to 50% of the HIV-infected population and subgroups respectively are estimated to be unaware of their HIV diagnosis. Perinatally-infected HIV-positive youth, aged 13-24 years, have survived unexpectedly into adulthood, have had unique HIV disclosure experiences and now face HIV disclosure issues of adulthood and perhaps parenthood. Despite new effective HIV therapies, no HIV prevention plan exists that has diminished the rate of new HIV infections. HIV stigma and lack of universal HIV reporting laws dissuade timely HIV disclosure. Missed HIV disclosure perpetuates HIV transmission and infection. Understanding the attitudes and beliefs of HIV disclosure among perinatally-infected HIV-positive youth and their caregivers may uncover reasons to HIV disclosure delays, avoidance and intentions. The Care to Share HIV Disclosure study was designed to identify the attitudes and beliefs of HIV disclosure among HIV-positve youth (aged 13-24 years), who were infected from birth and who knew their HIV diagnosis, along with their caregivers. Twenty-six participants (15 youth and 11 caregivers) completed the theory-based questionnaires of a 21-item multiple choice survey on HIV disclosure framed in the Theory of Reasoned Action and Theory of Planned Behavior and included an additional open-ended survey that applied the Transactional Model of Stress and Coping to address youth's and caregivers' HIV disclosure experiences. Youth were found to have a selective unfavorable HIV disclosure outcome when among referents of close friends. However youth did believe in HIV partner notification. For caregivers, it mattered who disclosed the HIV illness to the youth. HIV stigma was of concern based on the youths' tendency to believe in keeping HIV a secret and their caregivers' ambivalence to HIV secrecy. However, favorable HIV disclosure outcomes were identified for both youth and caregivers the potential for HIV disclosure: when seeking HIV knowledge, when around caregivers and close family and in situations of perceived controllability as when helping others learn about HIV. These findings unveil HIV disclosure attitudes and beliefs within this population and may reveal the attributes that may inhibit or promote HIV disclosure behaviors. HIV disclosure studies that address attitudes and beliefs among larger populations of youth and HIV-infected persons are necessary to identify effective individual, group and society approaches that would promote timely, responsible and meaningful HIV disclosure methods that promote a healthy identity and interrupt HIV transmission.^

Illicit drug use, alcohol use and nicotine dependence as predictors of antiretroviral adherence in a sample of HIV positive smokers

Objective. Predictors of non-adherence to antiretroviral medications in a population of low-income, multiethnic, HIV-positive smokers were investigated. ^ Methods. A secondary analysis was conducted using baseline data collected from 326 patients currently prescribed antiretrovirals enrolled in a randomized clinical trial assessing smoking outcomes. Variables evaluated included demographics, stress, depression, nicotine dependence, illicit drug use and alcohol use. ^ Results. The average age of participants was 45.9 years (SD=7.6). The majority of participants were male (72.1%), Black (76.7%), reported sexual contact as the method of HIV exposure (heterosexual (43%) and MSM (27%)) and were antiretroviral adherent (60.4%). Results from unadjusted analyses indicated depression (OR=1.02; 95% CI=1.00-1.04), illicit drug use (OR=2.39; 95% CI=1.51-3.79) and alcohol consumption (OR=2.86; 95% CI=1.79-4.57) were associated with non-adherence. Multivariate analyses indicated nicotine dependence (OR=1.13; 95% CI=1.02-1.25), illicit drug use (OR=2.10; 95% CI=1.27-3.49) and alcohol use (OR=2.50; 95% CI=1.52-4.12) were associated with nonadherence. ^ Conclusions. Illicit drug use, alcohol use and nicotine dependence are formidable barriers to antiretroviral adherence in this population. Future research is needed to assess how to address these variables in the context of improving antiretroviral adherence for individuals living with HIV/AIDS.^

Anal warts and their predictors among HIV-infected women

Human papillomavirus (HPV) is a necessary cause of cervical cancer and is also strongly associated with anal cancer. While different factors such as CD4+ cell count, HIV RNA viral load, smoking status, and cytological screening results have been identified as risk factors for the infection of HPV high-risk types and associated cancers, much less is known about the association between those risk factors and the infection of HPV low-risk types and anogential warts. In this dissertation, a public dataset (release P09) obtained from the Women's Interagency HIV Study (WIHS) was used to examine the effects of those risk factors on the size of the largest anal warts in HIV-infected women in the United States. Linear mixed modeling was used to address this research question. ^ The prevalence of anal warts at baseline for WIHS participants was higher than other populations. Incidence of anal warts in HIV-infected women was significantly higher than that of HIV-uninfected women [4.15 cases per 100 person-years (95% CI: 3.83–4.77) vs. 1.30 cases per 100 person-years (95% CI: 1.00–1.58), respectively]. There appeared to be an inverse association between the size of the largest anal wart and CD4+ cell count at baseline visit, however it was not statistically significant. There was no association between size of the largest anal wart and CD4+ cell count or HIV RNA viral load over time among HIV-infected women. There was also no association between the size of the largest anal wart and current smoking over time in HIV-infected women, even though smokers had larger warts at baseline than non-smokers. Finally, even though a woman with Pap smear results of ASCUS/LGSIL was found to have an anal wart larger than a woman with normal cervical Pap smear results the relationship between the size of the largest anal wart with cervical Pap smear results over time remains unclear. ^ Although the associations between these risk factors and the size of the largest anal wart over time in HIV-infected women could not be firmly established, this dissertation poses several questions concerning anal wart development for further exploration: (1) the role of immune function (i.e., CD4+ cell count), (2) the role of smoking status and the interaction between smoking status with other risk factors (e.g., CD4+ cell count or HIV RNA viral load), (3) the molecular mechanism of smoking on anal warts over time, (4) the potential for development of a screening program using anal Pap smear in HIV-infected women, and (5) how cost-effective and efficacious would an anal Pap smear screening program be in this high-risk population. ^

Clostridium difficile infection (CDI) in HIV-positive patients

The main aim of this study was to look at the association of Clostridium difficile infection (CDI) and HIV. A secondary goal was to look at the trend of CDI-related deaths in Texas from 1999-2011. To evaluate the coinfection of CDI and HIV, we looked at 2 datasets provided by CHS-TDSHS, for 13 years of study period from 1999-2011: 1) Texas death certificate data and 2) Texas hospital discharge data. An ancillary source of data was national level death data from CDC. We did a secondary data analysis and reported the age-adjusted death rates (mortality) and hospital discharge frequencies (morbidity) for CDI, HIV and for CDI+HIV coinfection.^ Since the turn of the century, CDI has reemerged as an important public health challenge due to the emergence of hypervirulent epidemic strains. From 1999-2011, there has been a significant upward trend in CDI-related death rates; in the state of Texas alone, CDI mortality rate has increased 8.7 fold in this time period at the rate of 0.2 deaths per year per 100,000 individuals. On the contrary, mortality due to HIV has decreased by 46% and has been trending down. The demographic groups in Texas with the highest CDI mortality rates were elderly aged 65+, males, whites and hospital inpatients. The epidemiology of C. difficile has changed in such a way that it is not only staying confined to these traditional high-risk groups, but is also being increasingly reported in low-risk populations such as healthy people in the community (community acquired C. difficile), and most recently immunocompromised patients. Among the latter, HIV can worsen the adverse health outcomes of CDI and vice versa. In patients with CDI and HIV coinfection, higher mortality and morbidity was found in young & middle-aged adults, blacks and males, the same demographic population that is at higher risk for HIV. As with typical CDI, the coinfection was concentrated in the hospital inpatients. Of all the CDI-related deaths in USA from 1999-2010, in the 25-44 year age group, 13% had HIV infection. Of all CDI-related inpatient hospital discharges in Texas from 1999-2011, in patients 44 years and younger, 17% had concomitant HIV infection. Therefore, HIV is a possible novel emerging risk factor for CDI.^

Quality of life and functional status in a low -income, multiethnic HIV -positive population

The introduction of new medical treatments in recent years, commonly referred to as highly active antiretroviral therapy, has greatly increased the survival of patients with HIV/AIDS. As patients with HIV/AIDS continue to live longer, other important health-related outcomes, such as quality of life (QOL), should be thoroughly studied. There is also evidence that racial/ethnic minorities are disproportionately affected by HIV/AIDS, but potential health disparities among individuals already infected with HIV/AIDS have not been adequately examined in ethnically diverse populations. The purpose of this dissertation was to: (1) examine the impact of both demographic and behavioral variables on functional status and overall QOL among a population of ethnically diverse and economically disadvantaged HIV/AIDS patients; (2) examine the psychometric properties of a functional status measure—the Household and Leisure Time Activities questionnaire (HLTA); and (3) assess a proximal-distal theoretical framework for QOL using a full structural equation model in a population of patients with HIV/AIDS. Analyses were performed using data collected in the fall of 2000 from the project, Health and Work-Related Quality of Life and Health Risk Behaviors in a Multiethnic HIV-positive Population . Investigators from The University of Texas M.D. Anderson Cancer Center, The University of Texas-Houston Medical School, and The University of Texas School of Public Health conducted this project. The study site was the Thomas Street Clinic (TSC), a comprehensive HIV/AIDS care facility funded by the Harris County Hospital District (HCHD). TSC provides HIV/AIDS care to a diverse population of approximately 4000 medically indigent residents of Harris County. A systematic, consecutive sampling procedure yielded a sample size of 348 patients. Findings suggested that overall QOL, work-role functioning, household functioning, and leisure time functioning were impaired in this patient population. Results from the psychometric evaluation indicated that the HLTA was a reliable and valid measure of household and leisure time functioning status in a low-income multiethnic HIV-positive population. Finally, structural equation modeling of the proximal-distal QOL model suggested that this model was not a viable representation of the relationship between the study variables in this patient population. ^

Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity.

When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.

Impfungen bei Immunsupprimierten. Mit Fokus auf HIV-positive Personen, Personen mit einer hämatologischen Stammzelltransplantation oder Organtransplantation und Personen mit funktionaler oder anatomischer Splenektomie

Personen mit einer HIV-Infektion, nach einer Organ- oder einer hämatologischen Stammzelltransplantation oder mit einer funktionalen oder anatomischen Asplenie sind gegenüber Infektionen anfälliger. Sie haben eine grössere Komplikationsrate und ein höheres Risiko für einen chronifizierten Verlauf. Impfungen wären eine ideale primäre Präventionsmassnahme, sind aber – durch dieselben Mechanismen des Immundefektes der zu schwereren Krankheitsverläufen führt – in ihrer Wirksamkeit vermindert. Die Impfungen sollen daher, wenn immer möglich, vor Beginn der Immunsuppression oder später zum Zeitpunkt der minimalsten Immunsuppression, durchgeführt werden. Trotzdem bleibt der Benefit von Impfungen bei immunsupprimierten Personen unbestritten, sofern die Indikationsstellung bezüglich Zeitpunkt und Dosierung (Dosismenge und -anzahl), die zu einem maximalen Ansprechen führt, beachtet wird. Lebendimpfungen sind wegen der Gefahr der unkontrollierten Vermehrung der Impfviren bei schwerer Immunsuppression kontraindiziert. Die Serologie soll unspezifischer gemessen werden, da schwer immunsupprimierte Personen im Falle einer relevanten Exposition durch passive Immunisierung mittels spezifischer oder unspezifischer intravenöser Immunglobuline geschützt werden können.