Current HIV Research - Volume 7, Issue 6, 2009

The use of intensive care units (ICU) resources for HIV-Infected patients has been controversial since the first reported cases, raising practical ethical and economic issues about aggressive treatment. The aim of this review of the literature is to provide current information on the epidemiology of human immunodeficiency virus (HIV)-infected patients admitted to ICU during the era of highly active antiretroviral therapy (HAART) and to highlight issues related to HAART that are relevant to the intensivist. Overall mortality of critically ill HIV-infected patients in ICU has decreased in the HAART era and patients are more commonly admitted with non-HIV-related illnesses. Use of HAART in ICU is problematic, however it may be associated with improved outcomes. More HIV-infected patients surviving ICU admission are more likely to need critical care for problems unrelated to HIV infection or for conditions related to HAART toxicity. Intensivists need to be familiar with HAART (i) to recognize life-threatening toxicities unique to these drugs; (ii) to avoid drug interactions, which are extremely common and potentially life-threatening; (iii) to avoid enhancing HIV drug resistance, an occurrence that could have devastating consequences for the patient following ICU discharge.

Screening everyone for HIV at least once is estimated to be cost-effective. Screening in health care settings is recommended to help achieve that goal. Health care settings often encounter the same patient repeatedly, and it is unknown if limited resources are better allocated to conduct repeat screening, or to screen patients not yet tested. We reviewed data for a targeted ED based HIV screening program for 2003-2007. The role of prior testing history as a predictor of undiagnosed HIV positivity was assessed using a negative binomial model adjusted for demographics and risk behaviors. HIV testing was provided to 8,450 unique patients. There were 5,781 (70%) self-reporting a prior HIV test. Compared with patients reporting no prior test, the relative risk of HIV positivity for those reporting a test within the prior year was 0.90 (95%CI 0.48-1.66), and for those reporting a prior test more than a year previously the relative risk was 0.91 (95%CI 0.48-1.73). Among patients testing positive, those who did not report a prior test had a median CD4 count that was 228 cells/mm3 lower than those with a prior test (CI95 of the difference in medians 20-436 cells/mm3). Diagnosis of prevalent HIV among those who are at risk but have never been tested should be a priority. However, repeat screening of target populations for incident infection remains important and results in earlier diagnosis. Recent self-reported testing history is not associated with undiagnosed positivity among targeted patients irrespective of the timing of the prior test.

Pulmonary arterial hypertension (PAH) is a life-threatening complication of HIV infection. The prevalence of HIV-associated PAH (HIV-PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). HIV-PAH treatment is similar to that for all PAH conditions and includes lifestyle modifications, general treatments, and disease-specific treatments. We reviewed the cases of HIV-PAH reported in the Literature in order to evaluate the role of HAART and specific PAH therapy in the prognosis and outcome of HIV-PAH. The research was performed through the PubMed database, by using the following key words: human immunodeficiency virus, AIDS, pulmonary hypertension, antiretroviral, and treatment. The outcome was reported as survival at the end of the observation period of each study. We found 509 patients with HIV-PAH described in the literature to date. At the end of follow-up period, survival rates were 55% and 22% among patients treated or not with antiretroviral therapy (ART), respectively (p = 0.02). Moreover, survival rates at the end of follow-up were 76% and 32% among patients treated or not with specific therapy for PAH (PAH-ST), respectively (p<0.0000001). Survival rates were 69% and 38% among patients treated or not with ART and PAH-ST, respectively (p = 0.02). Specific therapy for PAH should be strongly recommended in patients with HIV-PAH. The role of the HAART in influencing the outcome of HIV-PAH is controversial, even if some evidences seem to indicate a beneficial effect in the clinical course of the disease.

We designed a multicenter cross-sectional study to describe the epidemiological characteristics of the HIV-1- infected population aged 70 years or more in our setting. 179 individuals from eight university hospitals in Barcelona, Spain, were included, representing 1.5% of HIV-1 infected subjects followed during 2008. Most subjects were male (76%) and had acquired HIV infection through sexual intercourse (87%); 69% had been diagnosed with HIV-1 after their sixties. The CD4 cell counts at HIV-1 diagnosis were < 200 cells/mm3 in 52% of individuals, whereas this was only seen in 34% of subjects from a published cohort including younger HIV- infected adults from the same setting [1]. Most of our patients were on HAART, had undetectable HIV-1 viremia and the most recent median CD4 cell counts were ⋚ 350 cells/mm3. 154 subjects had at least one comorbid condition, including dyslipidemia (54%), hypertension (36%), hyperglicemia or diabetes (30%), cardiovascular disease (23%), chronic renal failure (18%), history of neoplasia (17%) and cognitive impairment (11%). Lipodystrophy was reported in 58% of individuals. Rates of hypercholesterolemia, diabetes and cancer were higher than those reported in unselected local population (28%, 17% and 7%, respectively). The study participants were taking an average of 2.97 drugs (range 1-10) other than antiretrovirals. In conclusion, the elder population infected with HIV-1 is likely being diagnosed late and at lower CD4+ counts and is frequently affected by comorbidities and co-medication. Based on our findings, we suggest some recommendations regarding the management of this growing population.

We described differential selective pressures along codon sites of the RT and PR genes of HIV-1 from HAART-failing and naive-treated individuals, through the comparison of the ratio of non-synonymous mutations (dN) to synonymous mutations (dS) substitution per site. Resistance-associated mutations were found in 1/71 (1.4%) and 109/117 (93.1%) samples from naive-treated and HAART-failing individuals, respectively, although most of positively selected codons represented polymorphisms in positions 123, 211, 245, 297 in RT and 37, 63 in PR of naive-treated samples and positions 122, 123, 245, 272, 277, 286, 297 in RT and 10, 15, 20, 35, 37, 62, 63, 64, 71, 72, 77, 93 in PR of HAARTfailing samples, except by ARV-resistance codons 74, 184, 215 in RT and 90 in PR exclusively found in HAART-failing group. The number and diversity of sites under selective pressure at populational level also increased in RT but not in PR of treated individuals. Our results demonstrated no evolution of drug-associated codons among untreated individuals, indicating unlikely transmission and adaptation of resistant HIV-1 strains in a free drug environment. Polymorphic sites observed exclusively in HAART-failing group, may contribute to HIV-1 escape and adaptation at individual and populational levels in a drug environment, although those mutually found in HIV-1 despite of previous exposure to ARV treatment, should not be considered accurate resistance markers.

Stigma within health care settings poses a considerable barrier to the provision of treatment and care for patients with HIV/AIDS (PLWHA). Southern China is located in a region with one of the world's fastest growing HIV/AIDS epidemics. Attitudes towards PLWHA amongst health workers are currently under-researched in this region. This paper examines the inter-relationships between prejudicial attitudes among Chinese medical students towards HIV/AIDS and attitudes towards three risk behaviors: injecting drug use (IDU), commercial sex (CS) and commercial blood donation (CBD). Medical students (N = 352) in Guangzhou were presented with two random vignettes; each describing a hypothetical male that was identical, except for the disease diagnosis (AIDS/leukemia) and the cocharacteristic (IDU/CS/CBD/blood transfusion/no co-characteristic). After reading each vignette, participants completed a standard prejudicial scale. Univariate and multivariable analyses revealed significant levels of prejudice associated with AIDS, IDU and CS. Regardless of the disease, patients with IDU or CS were judged significantly worse than patients who had received a blood transfusion. No significant interactions were found between AIDS and the stigmatized cocharacteristics. The findings suggest that prejudice towards PLWHA needs to be understood within the larger context of the stigma towards risk behaviors. Although non-significant interactions were found between AIDS and the stigmatized risk behaviors, the overlap between the local HIV/AIDS, IDU and CS populations suggests that addressing risk behaviorrelated prejudices could be critical for improving care and treatment for PLWHA.

A proportion of HIV-patients does not normally restore their CD4 counts despite virological response to HAART. Those whose CD4 counts persistently remain closed to the critical threshold for opportunistic infections deserve special interest. To study the risk factors, the long-term CD4 counts evolution, and the risk of death of patients who persistently maintain low CD4 counts, despite virological response to HAART, within a multicenter, hospital-based cohort study. A total of 147 patients were selected from CoRIS-MD and classified into a “Low-Group” or a “High- Group”, depending on their CD4 counts after two-years of effective HAART (threshold 250 cells/μL). Associated risk factors were analysed by logistic regression, the CD4 dynamics were evaluated over a total period of 7.70 years (IQR, 6.70-9.00), and mortality was estimated by Cox proportional hazard. A total of 40 patients (27%) were classified into the “Low-Group”. The odds ratio for this group increased with age, being 4.56 (2.23-9.33) for over 40, and was also higher among IDU, 3.63 (1.04-12.68). Six years thereafter, among these patients, only a 30% exceeded 350 CD4 cells/μL and a 12% exceeded 500 CD4 cells/μL. Furthermore, the “Low-Group” had a death rate of 2.42 per 100 persons/year (95%CI, 1.01-5.81), although once adjusted by age the estimates were no longer significant [4.14 (0.87-19.72)]. Our results suggest that those HIV patients who have not overcome the critical threshold of 250 CD4 cells/μL after a two years period of virologically effective HAART do persist with the aforementioned failure of CD4 restoration for a much longer time.

Although it is well known that antiretroviral drugs (ARVs) across the placenta in different extents, few data are available concerning the impact of the transplacental passage of ARVs on newborn outcome. The aim of this study is to evaluate the transplacental diffusion of ARVs and the clinical assessment of the newborn. Mother and cord lopinavir, nelfinavir, atazanavir and nevirapine plasma levels were determined by high-performance liquid chromatography. Newborn gestational age, weight, and Apgar score were recorded. Cord-to-mother ratio (C:M) was calculated to estimate the placental passage of ARVs. Preterm birth was defined as delivery at <37 weeks of gestation and low birth weight was defined as a birth weight of <2500g. Twenty-six HIV-infected pregnant women were enrolled. Nevirapine presented the highest C:M ratio (0.60 ± 0.19), the C:M ratio of nelfinavir and atazanavir was 0.37 ± 0.38 and 0.20 ± 0.14, respectively. The lopinavir level in the cord was undetectable. The observed prevalence rate of neonatal low birth weight and preterm delivery was 19,2% (n = 5) and 15.4% (n = 4), respectively. A significant linear regression analysis was reported between the C:M ratio and newborn birth weight (p = 0.01). Although the role of highly active antiretroviral therapy (HAART) in preventing mother-to-child transmission is indisputable, these data indicate a pharmacological rationale to the association between birth weight and highly active antiretroviral therapy during pregnancy.

In HIV clinical research, participants are typically sampled based on demographic and/or disease characteristics. As little is known about HIV-specific disability, we did not know whether this purposive type of sampling would be helpful and what characteristics (if any) should guide our sampling strategy. We describe using exploratory focus groups to determine a sampling strategy to investigate disability from the perspective of adults living with HIV. We conducted 4 focus groups with 23 men and women and asked participants to describe their health-related challenges and impact on their overall health. We analyzed data to determine whether health-related challenges differed based on age, gender, ethnocultural background, length of time since HIV diagnosis and antiretroviral use and if these characteristics should be considered when sampling. Participants described seven health-related challenges that appeared not to vary based on demographic or disease characteristics. Variations emerged in the way health-related challenges manifested and the strategies participants used to deal with these challenges. Consequently, we decided upon a broad theoretical sampling strategy for the subsequent interview phase. Exploratory focus groups may be a useful technique to determine a sampling strategy when exploring a new phenomenon in HIV qualitative research.

In the HAART era Kaposi's sarcoma (KS) remains the second most frequent tumor in HIV-infected patients worldwide, and it has become the most common cancer in Sub-Saharan Africa. In western countries the risk for KS in men having sex with men (MSM) is 5 to 10 times higher compared to other groups of individuals practicing other HIVrisk behaviors. Patients with KS in Sub-Saharan Africa have very high tumor burdens and rapid disease progression with a diminished life expectancy of less than 6 months. KS lesions are comprised of both distinctive spindle cells of endothelial origin and a variable inflammatory infiltrate, which suggests that KS may result from reactive hyperproliferation induced by chronic inflammation, and therefore it is not a true neoplasm. KS has a variable clinical course ranging from very indolent forms, requiring no or minimal therapy, to a rapidly progressive disease. Treatment decisions must take into consideration the extent and the rate of tumor growth, patient's symptoms, immune system conditions and concurrent HIV-related complications. Several different therapeutic options are available but the optimal therapy is still unclear. Highly Active Antiretroviral Therapy (HAART) including protease inhibitors (PI) may represent the first treatment step for slowly progressive disease; chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease, whereas maintenance (M)-HAART after systemic chemotherapy may be an effective anti-KS measure after debulking CT. The angiogenic nature of KS makes it particularly suitable for therapies based on targeted agents such as metalloproteinase inhibitors, angiogenesis inhibitors and tyrosine kinase inhibitors. The aim of this article is to provide an up-to-date review of the current status and perspectives of AIDS-related KS in the HAART era.

Despite availability of successful prevention strategies, HIV continues to spread at alarming rates, especially among women in developing countries. Vaginal microbicides offer a promising approach for blocking transmission of HIV when condom use cannot be negotiated with male partners. A major problem in the development of vaginal microbicides is chemically induced vaginal irritation, which can enhance the risk of HIV transmission. Evaluation of vaginal irritation prior to clinical trials typically uses an expensive and animal-intensive rabbit vaginal irritation model, which could be supplemented by measuring additional inflammatory biomarkers. We studied several immunological parameters as potential biomarkers of vaginal irritation, using the spermicides nonoxynol-9 and benzalkonium chloride as test microbicides. We measured amounts of cytokines, as well as inflammatory cells, in vaginal tissue lysates and on the vaginal surface. We observed that treatment with the selected microbicides increases quantities of the inflammatory cytokines interleukin-1β, CXCL8, and CCL2 in the vaginal tissue parenchyma, and of CCL2 on the vaginal surface. This observation was correlated with increases in macrophages in the vaginal parenchyma. We suggest that measurements of CCL2 and macrophages can serve as new inflammatory biomarkers to evaluate the safety of promising novel microbicides for prevention of HIV.

α-defensins are reported to be a soluble component of innate immunity actively participating in host defense against HIV. In order to further investigate the role of α-defensins in innate immunity during HIV infection, we analyzed CD8+ T lymphocytes and neutrophils obtained from 34 HIV-infected and 14 uninfected subjects. CD8+ T cells and neutrophils were labelled for evaluating α-defensin expression by flow cytometric analysis using a dual laser FACScalibur. Culture supernatants and plasma were also collected for ELISA quantification of α-defensins. The results showed a significantly increased production of α-defensins in plasma, neutrophils and CD8 T-lymphocytes of patients with HIV infection in comparison with healthy controls. The expression of α -defensins, by CD8+ cells probably reflects both the intrinsic production and the uptake from cocultured cells that release defensins. The upregulation of α-defensin expression within neutrophils could account for the increased release of such peptides in the systemic circulation. Antiretroviral treatment did not have any effect on plasma levels and expression of α-defensins by neutrophils. Overall, our findings suggest that the increased production/expression of α-defensins could be correlated with the chronic process of immune activation seen in HIV infection.

Objective: To evaluate the potential impact of the current global economic crisis (GEC) on the spread of HIV. Design: To evaluate the impact of the economic downturn we studied two distinct HIV epidemics in Southeast Asia: the generalized epidemic in Cambodia where incidence is declining and the epidemic in Papua New Guinea (PNG) which is in an expansion phase. Methods: Major HIV-related risk factors that may change due to the GEC were identified and a dynamic mathematical transmission model was developed and used to forecast HIV prevalence, diagnoses, and incidence in Cambodia and PNG over the next 3 years. Results: In Cambodia, the total numbers of HIV diagnoses are not expected to be largely affected. However, an estimated increase of up to 10% in incident cases of HIV, due to potential changes in behavior, may not be observed by the surveillance system. In PNG, HIV incidence and diagnoses could be more affected by the GEC, resulting in respective increases of up to 17% and 11% over the next 3 years. Decreases in VCT and education programs are the factors that may be of greatest concern in both settings. A reduction in the rollout of antiretroviral therapy could increase the number of AIDS-related deaths (by up to 7.5% after 3 years). Conclusions: The GEC is likely to have a modest impact on HIV epidemics. However, there are plausible conditions under which the economic downturns can noticeably influence epidemic trends. This study highlights the high importance of maintaining funding for HIV programs.