Advent Of HAART Research Articles

P–075 HAART exacerbates anti-Koch-induced reproductive toxicity via suppression of androgen and down-regulation of cGMP signaling

Abstract Study question Will highly active antiretroviral drugs (HAART) and antikochs impair reproductive function when used singly and concurrently? Summary answer HAART exacerbates antikoch-induced reproductive toxicity by stimulating testicular and penile oxido-inflammatory response. This was associated with suppression of androgen and down-regulation of cGMP signaling. What is known already Although the advent of HAART and antikochs has significantly improved the clinical status, life expectancy and quality of life of patients with HIV/tuberculosis, these drugs are with shortcomings. Studies have reported that HAART induces testicular toxicity and impairs sperm quality. Similarly, antikochs has been shown to trigger oxidative testicular and sperm damage. Available data have implicated HAART and antikoch in the pathogenesis of male infertility via oxidative stress-mediated mechanism. However, no study has reported the impact of the concurrent administration of both HAART and antikochs as seen in patients with TB/HIV co-infection on testicular function, sexual behaviour and fertility outcome. Study design, size, duration This is a prospective experimental study using animal model. Forty sexually mature inbred male Wistar rats of comparable age were used for the study. The study lasted 8 weeks. Participants/materials, setting, methods Animals were acclimatized for two weeks after which they were randomly allotted into four groups (n = 10). The control rats 0.5mL of distilled water as vehicle, anti-Koch-treated rats received a cocktail of anti-tuberculosis drugs (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol), HAART-treated animals received a cock-tail of antiretroviral drugs (Efavirenz, Lamivudine, and Tenofovir), while the HAART+antikochs-treated rats received treatment as HAART-treated as well as antikoch-treated. The doses of drugs used were the Human Equivalent doses for rats. Main results and the role of chance HAART exaggerated antikoch-induced increase in testicular lactate dehydrogenase activity, concentrations of lactate and uric acid, and reduced testicular sorbitol dehydrogenase activity. Furthermore, HAART worsens antikoch-induced decline in the activities of testicular and penile superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase, as well as glutathione concentration, but increased malondialdehyde levels in testicular and penile tissues, as well as penile and testicular DNA fragmentation. Similarly, HAART aggravates antikoch-driven reduction in penile cGMP, circulatory and testicular testosterone, serum prolactin, LH and FSH, impaired sperm quality, sexual behaviour, and fertility outcome. Limitations, reasons for caution This is a prospective study using animal model; hence findings should be extrapolated to human with care. Human studies are thus recommended. Wider implications of the findings: This study demonstrates for the first time the impact of HAART and antikoch, when used singly or in combination, on sexual behaviour, sperm quality and penile and testicular integrity. The findings add to the available literature by providing the molecular mechanism through which HAART and/or antikoch possibly impair reproductive function. Trial registration number N/A

The aspartate aminotransferase to platelet ratio index for assessing hepatic fibrosis in human immunodeficiency virus-hepatitis C virus coinfected patients: A local experience

Background: HCV infection is widespread among HIV infected populations because of their increased life expectancy with the advent of HAART. Hepatic fibrosis is one of the most robust prognostic factors used to predict HCV disease progression and clinical outcomes. This study's objective was to evaluate hepatic fibrosis using APRI in HIV-HCV co-infected individuals compared to HIV monoinfected. Methods: A total of 120 HIV infected patients (mean age 41.7±10.0 years) was enrolled in a study conducted in JNIMS, Manipur from August 2017 to August 2019. Liver fibrosis was assessed by the APRI which signifies the presence and absence of significant fibrosis if APRI > 1.5 and APRI < 0.5 respectively. Correlation between hepatic fibrosis and immunological status was established. Statistical analysis was done using SPSS version 21. Results: HIV-HCV co-infected patients had a higher abnormal mean AST level (114.18±150.19 IU/L) than HIV monoinfected (65.03±47.71 IU/L). The mean platelet count in HIV-HCV co-infected patients (106±38×103 cells/mm3) was lower than that of HIV monoinfected (207±80×103 cells/mm3). The mean APRI score in HIV-HCV co-infected patients (3.05±3.89) was higher than that in HIV monoinfected (1.02±1.38) indicating the presence of significant hepatic fibrosis in the co-infected group (p<.001). Conclusion: A high AST level combined with thrombocytopenia (APRI score>1.5) is an indicator of hepatic fibrosis in HIV-HCV co-infected individuals. Our study demonstrates that HIV-HCV co-infected patients and HIV related advanced immunosuppression is associated with higher APRI. Because of its simple, non-invasive and less costly nature, APRI may be utilised for assessing hepatic fibrosis in resource-limited settings.

329. Health Disparities Among HIV-Positive Patients with Kaposi’s Sarcoma

BackgroundKaposi’s sarcoma (KS) is an AIDS-related condition that is mediated by HHV-8. Although incidence and mortality of KS in the United States have decreased over time since the advent of HAART, there may be disparities in mortality based on geographic location and race/ethnicity, particularly African-American men in the South.MethodsA retrospective electronic medical record review was conducted using integrated inpatient and outpatient data in EPIC from PHHS. We included all individuals with a diagnosis of HIV and Kaposi’s sarcoma between January 1, 2009 and December 31, 2018 based on ICD-9/10 codes. We collected demographic information, HIV history, variables related to HIV and KS diagnosis, treatment and outcomes data for each patient. We calculated hazard ratios using Cox proportional hazards modeling.ResultsWe identified 252 patients with KS. 95% of patients were male, and the majority were MSM (men who have sex with men; 77% of all patients). 35% of patients were Hispanic, 34% were African-American and 31% were Caucasian. Over half (56%) of patients were funded through Ryan White or were uninsured. The median CD4 count and viral load at the time of cancer diagnosis were 44 and 73,450, respectively. 24% of patients were confirmed to have died by the end of the study time frame. However, due to loss to follow-up, 35% of the cohort had an unknown vital status at the time of the final chart review. Variables most strongly associated with mortality were >2 hospitalizations in the first 6 months of cancer diagnosis (aHR=4.93, P = 0.0003), IV drug use (aHR=3.61, P = 0.0009), and T1 stage of KS (aHR= 2.13, P = 0.0264). African American patients had lower survival than Caucasian or Hispanic patients, with a 5-year survival of 69%, 81% and 80% respectively, although this did not reach statistical significance (aHR 1.77, P = 0.1396).ConclusionWe describe a large cohort of patients with HIV and HHV-8-related disease, who are predominantly of minority race/ethnicity, uninsured, and have advanced HIV disease. Factors associated with mortality include Black/African-American ethnicity, number of hospitalizations, IV drug use and T1 stage of KS. Our mortality analysis is limited due to high lost to follow-up rates, so we suspect overall mortality in our cohort is higher than currently reported. DisclosuresAnk E. Nijhawan, MD, MPH, Gilead Sciences, Inc.: Research Grant.

A rare case of musk myasthenia gravis in a HIV patient

Autoimmune disorders have been frequently described in HIV patients but there has been little research on the association between HIV and myasthenia gravis. MuSK myasthenia gravis coexisting with HIV is an even rarer entity. 50 years old lady with HIV and baseline CD4 count of 170, on antiretroviral therapy from 1.5 years, presented with complaints of difficulty swallowing, change in voice and intermittent double vision since 10 months. There was a history of fluctuations. On examination she had bilateral mild lateral gaze palsy with mild asymmetric bifacial weakness. Her gag reflex was weak on both sides. Her CD4 count done 6 months back had increased to 477 and her MRI brain was normal. Myasthenia gravis was strongly suspected. Repetitive Nerve Stimulation showed a decremental response in bilateral median innervated muscles. Her MuSK antibody was positive and Ach receptor antibody was negative, which confirmed the diagnosis of MuSK myasthenia gravis. There was improvement with addition of pyridostigmine and she was later discharged on Pyridostigmine, Prednisolone and Azathioprine. On follow up, the patient is showing sustained improvement. Autoimmune disorders are being increasingly reported with HIV infection since the advent of HAART. MuSK myasthenia gravis with HIV has been reported in very few case reports. The use of immunosuppressants in the treatment of these conditions should be carefully evaluated.

Stigmatization and discrimination towards people living with HIV/AIDS attending antiretroviral clinic in a centre of excellence in HIV care in India

Background: HIV/AIDS is a serious challenge globally. Plethora of morbidities due to crippling immune system reduces quality of life (QOL). The advent of HAART has changed this deadly disease to a chronic manageable illness with focus shifting from fighting virus to ensuring a good QOL. Objective of the study was to assess stigma and discrimination among PLHA and factors influencing, if any in Indian setting.Methods: A cross sectional study was carried out among 220 male aged &gt;15 years (PLHA) attending ART centre of centre of excellence in HIV care in India (CSTM, Kolkata) from May 2012-April 2013 using a pre-designed and pre-tested schedule regarding socio-demographic characteristics and social stigma. Statistical analysis was done using SPSS version 16.0 and p&lt;0.05 was considered as significant.Results: Nearly half (45%) and one-fifth (20.9%) of the study population were discriminated by the family and community respectively. Most (74.5%) of the study population had disclosed their HIV status to their family members. Maximum participants (96.4%) agreed that those who know their HIV status will tell that to others. In the multivariate model with increase in PCI the odds of score of dependant variable increases, so the odds of social stigma decrease (as increase in score means decrease in social stigma).Conclusions: The results show that factors associated with stigma should be further explored as it’s important in considering public health interventions to improve care of PLHA in India.

Initial Experience with Thrombopoetin Receptor Agonists (TRA) in 5 Patients with Refractory HIV-Associated Immune Thrombocytopenic Purpura (ITP)

Introduction: In the pre-highly active anti-retroviral therapy (HAART) era, ITP was a relatively common hematologic abnormality, which was seen in as many as 30% of patients infected with HIV. With the advent of HAART, the incidence of HIV-associated ITP has been reduced substantially, with some epidemiological studies showing contemporary rates as low as 1 to 3% (Vannappagari, Platelets 2011). In cases where HAART does not lead to adequate improvement in platelet counts, next lines of therapy have traditionally consisted of corticosteroids, including dexamethasone and prednisone, intravenous immunoglobulin (IVIG), anti-Rho(D) immune globulin, rituximab and, in the current era, more sparingly, splenectomy. When platelet counts remain persistently <20 x 109/L despite medical and surgical interventions, patients with ITP retain a heightened risk of bleeding complications (Frederiksen, Br J Haematol 2014). The TRAs eltrombopag (Promacta®) and romiplostim (Nplate®) are effective in 59% to 88% of ITP cases in patient without HIV, and loss of response while on continued therapy is uncommon. The agents’ use in treatment of refractory HIV-associated ITP has not, however, been sufficiently studied or reported.Methods: Herein we perform a retrospective chart review of 5 patients with HIV-related ITP treated from 2009-2014. All 5 patients with HIV-associated ITP had failed at least two lines of ITP therapy before they received a TRA (table). Mean age was 34 years (18-47), 3 males and 2 females. 4 patients had CD4+ counts >200 cells/ µL, viral loads < 40 copies/mL, and platelet counts ≤20 x 109/L before starting TRA therapy.Results: Each patient responded to TRA use with a mean pre-treatment platelet count of 15 x 109/L, and this increased to a mean of 110 x 109/L 6 weeks following treatment initiation. 2 of the patients have maintained a sustained response with adequate platelet counts 3 years after discontinuing TRA therapy. 1 patient succumbed to a myocardial infarction while on eltrombopag and 1 patient, while on romiplostim, expired from complications of a presumed pulmonary embolus after undergoing lumbar spine surgery.Abstract 5014. Table:Characteristics of HIV-related ITP patients given TRACaseNadir CD4+ count (cells/µL) /HIV viral load (copies/mL)HAART RegimenCD4+ count (cells/µL) /HIV viral load (copies/mL) at time of use of TPAPlatelet count pre-TRA treatmentLines of ITP treatment before TRATRA (dose where response was observed and sustained)6 month f/u platelet countSustained Response after stopping TRA (duration)Case 1261/ 5,000Atripla®340 / <4020 x 109/L1. Pred + IVIG 2.Rituximab + DexRomiplostim (4µg/kg)158 x 109 /LYes (3 years)Case 2a284/ 74,743Atripla®300/ <402 x 109/L1. Pred 2. Pulse Dex 3.Rituximab + Dex 4. IVIGRomiplostim, then Eltrombopag (50mg)N/AN/ACase 3261/ 5,000Atripla®>300 / <4013 x 109/L1. Pred + IVIG 2.Rituximab + DexRomiplostim (2µg/kg)128 x 109 /LYes (3 years)Case 4100/ 100,000Zidovudine + Epivir + Nevirapine180 / <4039 x 109/L1. IVIG 2. Pred 3. RituximabRomiplostim (3µg/kg)52 x 109 /LbN/ACase 5100/ 2,400Truvada + darunavir + detravirine + raltegravir + ritonavir>200 / 54,00013 x 109/L1. Anti-Rho(D) 2. IVIG 3. Rituximab 4. Pulse Dex 5. Pred 6.Rituximab + Dex Eltrombopag (50mg)48 x 109 /LcNoaPatient expired prior to 6 month f/u due to myocardial infarction bPatient sustained response for 2 weeks after discontinuation of TRA cPatient to be reinitiated on maintenance therapy due to lack of compliance Abbreviations: efavirenz, tenofovir, and disoproxil fumarate (Atripla®); prednisone (Pred) dexamethasone (Dex); follow-up clinic visit (f/u)Discussion: Due to insufficient evidence, a definitive association between TRA use and the two patients who suffered thrombotic events remains speculative. Nonetheless, these events emphasize the importance of using these TRAs cautiously during periods of heightened risk of thrombosis such as post-surgery and during periods of immobility, or in patients with risk factors for thrombotic complications. While HIV-associated ITP remains an important clinical problem in the era of widespread HAART use, the availability of both romiplostim and eltrombopag give medical providers additional options in treating this disease. Further experience is needed, however, to better determine the effectiveness and, most importantly, the safety of these drugs in the context of HIV-associated ITP. DisclosuresNo relevant conflicts of interest to declare.

The clinical management of HCV in the HIV-infected patient.

Chronic hepatitis C affects an estimated 170 million persons worldwide and due to shared transmission routes many persons are coinfected with HIV. Since the advent of HAART, HIV patients have longer life expectancy and suffer fewer AIDS-related complications. The result has been an increase in morbidity and mortality from HIV-associated non-AIDS conditions, with high rates of liver-related deaths resulting from HCV in the coinfected population. Coinfection with HIV is an independent predictor of liver disease progression, and proper staging of fibrosis is of critical importance in the coinfected patient. In contrast to HIV, it is possible to eradicate HCV infection; and undetectable viral load 12 weeks after cessation of therapy, or sustained viral response (SVR), is considered a clinical cure. As achievement of SVR has been associated with significantly reduced mortality from liver disease and liver disease complications, it is imperative that patients coinfected with HIV-HCV receive therapy for their HCV infection. The length of therapy with previously available interferon-based regimens added a significant burden to HIV-HCV-coinfected patients. Newer, all-oral, interferon-free regimens promise to simplify treatment regimens, reduce side-effect profiles, and demonstrate reduced drug interactions with numerous HAART regimens.

Circulating mediators of inflammation in AIDS-related non-Hodgkin lymphoma.

86 Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries, accounting for 3-6% of AIDS-defining illnesses and 23-30% of AIDS-related mortality. The risk of developing NHL is estimated to be 60 times greater in HIV-infected individuals in comparison to the general population and this rate has remained elevated despite the advent of HAART. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male patients diagnosed with high-grade B-cell NHL. Controls were matched to each case from among those participants who developed an AIDS-defining opportunistic infection in the absence of any malignancy. Matching criteria included age and CD4+ cell count. Sera obtained from each patient near the time of NHL or AIDS diagnosis was tested for a panel of 171 serum biomarkers using multiplexed bead-based immunoassays. Biomarker measurements were evaluated to identify significant alterations between the experimental groups, correlations with disease progression and interactions between biomarkers. Results: A subset of 21 biomarkers was identified to be significantly altered in A-NHL cases in comparison to the AIDS controls. This subset included cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators. Many of the biomarkers included in this subset were positively correlated with disease progression. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in response to persistent immune stimulation and inflammation. A network of inflammatory mediators was identified demonstrating correlations with disease progression and overexpression in A-NHL patients. Further analysis of these biomarkers should enhance our ability to diagnose, monitor, and treat this disease.

Cardiometabolic risk, insulin resistance and immunity in HIV/AIDS patients receiving highly active retroviral therapy

Prior to the advent of HAART (Highly Active retroviral therapy), studies of insulin resistance in HIV infection showed normal insulin sensitivity. The metabolic disturbances due to HAART are now reported in our setting. To investigate potential associations between cardiometabolic indices, innate and adaptive immunity, adipokines, and markers of insulin resistance (IR) in HIV/AIDS patients on first-line antiretroviral therapy (ART) were studied. This cross-sectional study selected HIV/AIDS patients treated with ART at public clinics of Mthatha Municipality, South Africa. Age, waist-to-hip ratio, blood pressure, total cholesterol (TC), HDL-C, LDL-C, triglycerides, C-peptide, uric acid, C-reactive protein (CRP), glucose, and albuminuria were the cardiometabolic indices. Innate immunity (lymphocytes), adaptive immunity (CD4 cell count), adipokines (adiponectin, leptin), and insulin resistance markers—fasting serum Insulin and homeostasis model assessment—IR score were also explored. Out of 258 selected patients, aged 38.1 ± 9.3 years, 79.5 % were females. There was a univariate correlation between HOMA-IR score and triglyceride (r = 0.331; P < 0.0001), uric acid (r = 0.386; P = 0.008), albuminuria (r = 0.316; P < 0.0001), adiponectin (r = −0.322; P = 0.035), lymphocytes (r = 0.186; P = 0.04) and waist-to-hip ratio (r = 0.217; P = 0.013), and HOMA-IR score. C-peptide was correlated with serum Insulin (r = 0.694; P < 0.0001). After adjusting for confounding factors, only triglycerides and C-Peptide independently and significantly explained 64.1 % of the variance in HOMA-IR score. Patients receiving ART are at higher risk for diabetes mellitus, cardiovascular disease and chronic renal disease. Regular monitoring of patients on first-line anti-retroviral agents is imperative to detect these cardiometabolic risk factors and allow for treatment to be initiated early.

The Rising Challenge of Non-AIDS-Defining Cancers in HIV-Infected Patients

Since the advent of HAART, patients with HIV infection have seen a significant improvement in their morbidity, mortality, and life expectancy. The incidence of AIDS-defining illnesses, including AIDS-defining malignancies, has been on the decline. However, deaths due to non-AIDS-defining illnesses have been on the rise. These so-called non-AIDS-defining cancers (NADCs) include cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin's lymphoma. It is poorly understood why this higher rate of NADCs is occurring. The key challenge facing oncologists is how to administer chemotherapy effectively and safely to patients on antiretroviral therapy. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on the epidemiology and etiology of NADCs, as well as ongoing research into this evolving aspect of the HIV epidemic.

Abnormal Levels of γ-Glutamyl Transpeptidase (GGTP), ALT, AST in Human Immunodeficiency Virus-1(HIV-1) Infection

Background: Human Immunodeficiency Virus infection is associated with direct inflammation of hepatocytes leading to liver damage. Antiretroviral therapy, co-infection with other hepatotropic viruses, tumors, parasitic infestation and non-antiretroviral therapeutic drugs may also cause considerable hepatic damage in Human Immunodeficiency Virus infection. Hepatomegaly was seen as a common feature in both HIV infected asymptomatic and AIDS cases. With the advent of HAART, though the morbidity and mortality associated with HIV infection has considerably reduced, the cause of concern is the adverse drug reactions, hepatotoxicity, dyslipidemia and disturbed metabolism. Methods: The study was carried out at Apollo Health City, a tertiary care hospital between June 2010 to May 2011, which included 36 HIV seropositive and antiretroviral therapy naive individuals and 21 HIV seropositive patients presently on HAART since 3-4 months attending Integrated Counseling and Testing Centre (ICTC) situated at Area hospital Siddipet were enrolled in the study. A total of 25 Normal healthy individuals are included in the study as controls. The study group were screened for Hepatitis B and C viruses and excluded from the study if found positive for any of the hepatotropic viruses. Results: The study results showed serum concentrations of γ-Glutamyl Transpeptidase (GGTP), AST and ALT in HIV seropositive patients who are antiretrotherapy naive patients as 60.57±33.58, 22.25±11.85 and 35.14±30.11 respectively as compared to normal controls. Conclusion: The study results have clearly shown abnormal liver function tests in HIV patients who are not on HAART and revealed raised levels of serum GGTP, ALT and AST as compared to the normal healthy individuals. Results also have implicated the role of HAART in initiating liver damage even in the absence of other hepatotropic viruses as revealed by other studies. The influence of these and other factors, on the clinical progression of HIV infection should be reviewed in detail, both preceding and following treatment initiation [29].

HIV Status Does Not Impact on Outcome in Patients with Hodgkin Lymphoma Treated with ABVD Chemotherapy in the HAART Era,

Abstract 3646 Background:The prognosis of patients with HIV and non-Hodgkin lymphoma (NHL) has improved considerably since the advent of HAART, approaching that of patients with NHL in the general population when treated with the same chemotherapy regimens. However, it is not clear whether the same holds true for patients with Hodgkin lymphoma (HL). Aim: To analyze the outcome of patients diagnosed with HL treated with ABVD in the HAART era according to HIV status. Patients: From 1997 to 2010, 237 patients (92 with HIV infection) were newly diagnosed with HL at 5 university hospitals in London and consecutively treated with ABVD chemotherapy. Patients with HIV were older (median age: 41 years vs 31, p<0.001) and more were men (88% vs 59%, p<0.001). The histology subtype was more frequently mixed cellularity in HIV patients (54%) than in non-HIV (19%, p<0.001). In addition, HIV positive patients had more advanced stage at diagnosis (stage III-IV: 80% vs 33%, p<0.001), B-symptoms (81% vs 36%, p<0.001), lower Hb level (<10.5g/dL: 46% vs 20%, p<0.001) and lower albumin level (<4g/dL: 76% vs 35%, p<0.001). Patients with HIV infection had more frequently high risk disease according to the International Prognostic Score than HIV negative patients (IPS>3: 71% vs 22%, p<0.001). Amongst HIV patients, the HIV viral load (VL) was undetectable at the time of HL diagnosis in 52 of 86 patients with available data. The median VL for the remainder was 4,563 (range: 3,060–6,066). Forty-seven patients (53%) had a CD4 count <200/mL. All patients were treated with 4–6 cycles of ABVD chemotherapy with or without radiotherapy to residual/bulky areas according to local policies. Ninety patients with HIV infection received HAART concomitantly during chemotherapy. Results: The complete response (CR) rate in HIV positive and negative patients was 74% and 81%, respectively (p=NS). Fifty-one patients (21%) received consolidation radiotherapy. After a median follow-up of 59 months (range: 8–172 months), 40 patients relapsed at a median time of 7 months (range: 1–106). The median duration of response for HIV positive and negative patients was 33 months and 48 months, respectively (p=NS). Thirty-three patients have died: in 25 cases of HL; 2 patients due to toxicity and 5 patients due to other causes. Five-year event-free survival (EFS) was 59% (95%CI: 46–69) for HIV patients and 65% (95%CI: 56–72) for the remainder (p=NS). Five-year overall survival (OS) was 79% (95%CI: 67–87) and 88% (95%CI: 80–92) for HIV positive and negative patients respectively (p=0.06). HIV status did not predict OS or EFS on multivariate analysis including all variables comprising the IPS and HIV status. Conclusions: This long follow-up study demonstrates that patients diagnosed with HL in the setting of HIV infection have a more extensive disease with adverse prognostic factors. However, when treated with ABVD chemotherapy HIV positive status does not adversely affect OS or EFS. Disclosures:Montoto:Roche: Honoraria; Genentech: Research Funding. Orkin:Janssen: Honoraria; Gilead: Honoraria; BMS: Honoraria; BI: Honoraria; MSD: Honoraria; GSK: Honoraria; Viiv: Honoraria. Gribben:Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria.

HAART Does Not Improve the Outcome of HIV-Related Multicentric Castleman Disease: Results of a Multicentric Retrospective Study

Abstract 4918 Background.Multicentric Castleman Disease (MCD) is a rare lymphoproliferative disorder, strictly related to Kaposi Sarcoma (KS) as both associated to HHV-8 infection. Like other HIV-related diseases, such as Non Hodgkin Lymphoma (NHL) and Primary Central Nervous System Lymphoma, MCD prevalence is known to be increased in HIV-pos subjects. However, limited case series among this subset of patients (pts) are reported and data regarding epidemiological variations in the pre and post HAART era are often non conclusive. In order to evaluate possible differences between pre- and post-HAART era, we retrospectively evaluated epidemiological and clinical characteristics of all pts affected by HIV-pos MCD afferent to two Italian Institutions. Patients and Methods.Data concerning biological, clinical and prognostic factors of HIV-pos MCD pts were collected and reported on a database. Pts were grouped according to the date of diagnosis in pre- (before 1997) and post-HAART (after 1997) era. Results.During a 21-year period (1990-2011), 35 HIV-pos MCD pts were observed at our Institutions, nine in the pre- and 26 in the post-HAART era. Male/Female ratio was 30/5; median age 37y (23-65). Histological subtype in 34 evaluable cases was hyaline-vascular in 6, plasmacytic in 20 and mixed cellularity in 8. Median time interval from HIV-pos detection to MCD diagnosis was 24 months (range 0–157) and CD4 count at MCD diagnosis 233/mcL (26-839). All these MCD baseline characteristics were not statistically different between pre- and post-HAART era. A concomitant diagnosis of KS was made in 18/35 (51.4%) cases, all but one in the post-HAART era. NHL was diagnosed concurrently with MCD in 2/35 (5.7%) pts (1 Primary Effusion Lymphoma, PEL, and 1 Plasmablastic Lymphoma, PBL); in 8/35 (22.8%) cases NHL developed after MCD diagnosis (2 PEL, 1 PBL, 2 Diffuse Large Cell, DLC, 1 unspecified, respectively). Median time from MCD to NHL was 19 mo (0-71). Evolution toward NHL was observed in 3 (33%) cases in the pre-HAART era and in 5 (19%) in the post-HAART era (p=0.39, Fisher’s exact test). Six pts did not receive any type of treatment, 6 were treated with HAART only and 23 with different therapies, including antivirals, steroids, chemotherapy and rituximab (alone in 1 pt, in combination with chemotherapy in 5). Nineteen/23 pts received HAART together with other therapies. Two pts treated with rituximab developed NHL (1 PEL and 1 DLC). A complete or partial radiological response, together with clinical improvement was observed in 19/25 of evaluable pts (76%). Thirty pts were evaluable for relapse/progression, mainly in the post-HAART era. Overall, 19/30 pts showed MCD progression or transformation to NHL; median PFS was 15 months. Nineteen pts died and 5 were lost to follow-up. Overall survival (OS) of the entire series was 28 months, without significant differences between pre and post-HAART era (18 and 28 months, OR 0.643 [CI 0.2406–1.045], median follow-up 18 and 9 months, respectively). Causes of death were evaluable in 18 cases: NHL (7), MCD (6), opportunistic infections (1), liver cyrrhosis (1), acute myocardial infarction (1), KS (1) and therapy-related toxicity (1). NHL and MCD were the most frequent cause of death in the post-HAART era (4 and 5 of the 10 cases, respectively). Although no differences in OS between MCD pts without or with NHL were seen (19 vs 28 months, OR 0.6786 [CI 0.2763–1.081], median follow-up 13 and 23 months, respectively), eight/10 pts with NHL died, in comparison with 11/21 pts without NHL evaluable for outcome and median time from NHL diagnosis to death was 2 months (0-31). Conclusions.Our data confirm that the prognosis of HIV-related MCD remains poor even after the advent of HAART. Unlike other lymphoproliferative disorders, HAART did not impact on outcome of HIV-related MCD, suggesting that MCD can “escape” immune reconstitution. A concomitant diagnosis of NHL and uncontrolled MCD seem to be the main reason for an unfavourable outcome, particularly in the post-HAART era. New therapeutic approaches, including rituximab, should therefore aim at avoiding NHL transformation and controlling “MCD-related cytokine storm”. Disclosures:No relevant conflicts of interest to declare.

The pattern of medical mortalities in a specialist hospital in north-central Nigeria.

Review of causes of morbidity and mortality in health care facilities is an important exercise which gives a picture of the prevailing disease pattern in the particular community and at the same time looks out for any change in the disease pattern over time. This exercise is a necessary component for planning of the health care needs of the community. To determine the mortality pattern on the medical wards of the Kogi State Specialist Hospital, a tertiary center located in Lokoja, North-Central Nigeria. A retrospective review of medical records of all patients admitted to the medical wards of the hospital over a period of 18 months (December 2008 - May 2010) was carried out. The information recorded from these sources included the age and gender, diagnosis/ cause of death and the duration of admission. A total of six hundred and eighty-four patients were admitted during the period being studied with a predominance of female patients (Female: Male Ratio = 1.07). There were seventy-six deaths (11.1%) during the period in question with HIV and related complications accounting for most recorded mortality (32.9%) closely followed by non-communicable cardiovascular conditions (hypertension, heart failure and CVD) - 28.9%. This study clearly shows that HIV infection and its complications remains the leading cause of death despite the advent of HAART. Clearly there is a need to revisit the strategies of HIV prevention and control. Also there is an urgent need to focus on the prevention and treatment of non-communicable diseases like hypertension and diabetes.

Human Immunodeficiency Virus Infection and Hodgkin's Lymphoma in South Africa: An Emerging Problem

Hodgkin's lymphoma (HL) occurs with increasing frequency in human-immunodeficiency-virus-(HIV-) infected individuals. The natural history and behaviour of HIV-HL is different, being more atypical and aggressive. The association between HIV and HL appears to be primarily EBV driven. HAART use does not significantly impact on the incidence of HL. Indeed, the risk of HL has increased in the post-HAART era. However, the advent of HAART has brought renewed hope, allowing standard therapeutic options to be used more optimally, with better treatment outcomes. Despite the renewed optimism, the overall survival of HIV-HL patients remains less favourable than that in HIV-seronegative patients. This is particularly true in sub-Saharan Africa, where there is a significant burden of HIV/AIDS and where more than half the patients are HAART naive at diagnosis of HL. The similarities and differences of a South African cohort of HIV-HL are presented in this paper.

Prevalence of HIV among general surgical patients in southeastern Nigeria

Background With the advent of HAART, many HIV patients are now living longer. It is expected that the incidence of HIV-related malignancies will increase, with additional burden of operating on HIV patients in areas of chronic severe shortages where minimum basic precautions may not always be feasible. We decided to assess the HIV prevalence in surgical patients and compare the periods 2001-04 and 2008-09.

HIV Treatment in the Criminal Justice System

The advent of HAART has resulted in a dramatic decline in HIV-related morbidity and mortality among those accessing HIV treatment [1]. Fortunately, efforts to simplify regimens and scale up treatment systems have led to individuals being engaged in treatment in numbers and locales that were unimaginable just 10 years ago. Still, some seropositive populations have not benefited equally from advancements in HIV treatment. Studies of HIV-seropositive individuals who use injection drugs (IDU) on HAART confirm that adherent individuals can derive similar benefits as adherent individuals from other risk groups [2]. Nevertheless, coverage of HAART among IDU remains low, not only in areas such as the Russian Federation and other countries of the former Soviet Union and China, where a substantial and increasing proportion of new infections are linked to injection drug use, but also in settings with advanced healthcare systems [3]. Once on HAART, HIVseropositive IDU often achieve lower levels of adherence and are more likely to prematurely discontinue therapy [4,5]. As a result of the individual and, likely, community [6] benefits of attracting and maintaining IDU on HAART, there is an urgent need to identify and remove barriers to access and adherence to HAART among IDU [7].

Chronic exposure to nicotine and saquinavir decreases endothelial Notch‐4 expression and disrupts blood‐brain barrier integrity

Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia.

Changing patterns of AIDS: impact on the indications and diagnostic yield of bone marrow biopsies

After the advent of HAART, the clinical course of HIV infection has dramatically improved. Therefore, it seems appropriate to reevaluate the performance of bone marrow biopsy (BMB) as a diagnostic tool. The aim of the present study was to compare the reasons for performing a BMB and its diagnostic yield in HIV-patients before and after HAART. A total of 165 BMB specimens obtained from HIV-infected patients receiving care at the Hospital of Universidade Federal do Rio de Janeiro in two different periods (1986-1994 and 1999-2004) were analysed. The main reason for BMB examination in the first period was fever (88%), which decreased in the second period (57%, p < 0.0001), when cytopenia (51%) was the leading reason for BMB, whereas in the first period it accounted for only 30% (p = 0.008). A definitive diagnosis (infection, granulomas or lymphomas) was obtained in 28% of patients in the first period and in 19% during the second period (p = 0.20). The diagnosis turned out as infections decreased from 16% in period 1 to 2% in period 2 (p = 0.003). Despite the the limitations in the evaluation of fever, the use of BMB must be considered on an individual basis, whenever less invasive alternatives have been exhausted, and should be complemented by a bone marrow aspiration for microbiological studies.

HIV/AIDS epidemic features and trends in setif city (Algeria) from 1986 to 2009

Results The HIV epidemic started in SETIF in 1986 with the first diagnosed AIDS cases. The number of cases slowly but steadily increased, to reach, by 2009, 152 cases. The median age of infected persons was 39,77 years. 40.8% were WOMEN; The most frequent mode of transmission is sexual (76,9% of all cases; with mainly heterosexual transmission 77.9 percnt; with a strong correlation to travel and migration 37.20%). the proportion of persons diagnosed late (within 12 months before AIDS diagnosis) was 82,3%; 91.4% of married men (36) have sexual relationships outside marriage as compared to 0.0% of married women(27). We report also 13.60% discordant couples among married patients, Among documented HIV-positive mothers (36), their children were screend in 61.10%, and 95.5% of them were seronegatif, 55,9% of all cases were treated with ARV. HIV/ AIDS deaths 36,2% decreased markedly from 2002, associated with the advent of HAART.