Trends in mortality in people with HIV from 1999 to 2020: a multi-cohort collaboration.

BACKGROUND: Mortality among people with HIV declined with the introduction of combination antiretroviral therapy. We investigated trends over time in all-cause and cause-specific mortality in people with HIV from 1999-2020. METHODS: Data were collected from the D:A:D cohort from 1999 through January 2015 and RESPOND from October 2017 through 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV (CoDe), were calculated. Poisson regression models were used to assess mortality trends over time. RESULTS: Among 55716 participants followed for a median of 6 years (IQR 3-11), 5263 participants died (crude mortality rate [MR] 13.7/1000 PYFU; 95%CI 13.4-14.1). Changing patterns of mortality were observed with AIDS as the most common cause of death between 1999- 2009 (n = 952, MR 4.2/1000 PYFU; 95%CI 4.0-4.5) and non-AIDS defining malignancy (NADM) from 2010 -2020 (n = 444, MR 2.8/1000 PYFU; 95%CI 2.5-3.1). In multivariable analysis, all-cause mortality declined over time (adjusted mortality rate ratio [aMRR] 0.97 per year; 95%CI 0.96, 0.98), mostly from 1999 through 2010 (aMRR 0.96 per year; 95%CI 0.95-0.97), and with no decline shown from 2011 through 2020 (aMRR 1·00 per year; 95%CI 0·96-1·05). Mortality due all known causes except NADM also declined over the entire follow-up period. CONCLUSION: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts decreased between 1999 and 2009 and was stable over the period from 2010 through 2020. The decline in mortality rates was not fully explained by improvements in immunologic-virologic status or other risk factors.

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV.

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers.

Implementation of EACS vaccination recommendations among people living with HIV.

OBJECTIVES: With modern combination antiretroviral Treatment (cART) a normal life expectancy among people living with HIV (PLWH) has become reality if started early enough prior to the onset of more pronounced immunodeficiency. Therefore, prevention measures against other infectious diseases among this vulnerable group have gained increased attention. Indeed, the EACS guidelines recommend vaccinations against HAV, HBV, HPV, Influenza, Neisseria meningitidis, Streptococcus pneumoniae and VZV in HIV-infected adults. METHODS: All PLWH under cART attending our ID outpatient clinic between April to June 2018, were assessed during consultation for vaccination status regarding pneumococcus, Hepatitis A and B, influenza, varicella, meningococcus and HPV using a pre-defined questionnaire, vaccination certificates and medical records. In addition, the cohort database was screened for Hepatitis A and B serology and HIV surrogate markers. RESULTS: A total of 305 PLWH (82.3% male, 17.7% female) was included, median age was 48 years (IQR 47-51). Median CD4 + T cell count was 543 (IQR 304-770), and for 297 (97.4%) PLWH CD4 + T cell count was ≥ 200/ul. The viral load was undetectable (< 40 copies/ml) in 289 (94.8%) cases. Highest vaccination rates were observed for HAV (87.4%), Streptococcus pneumoniae (77.4%) and Influenza (76.5%). 64.3% PLWH got vaccinated against HBV, whereas VZV vaccination only played a minor role, in the context of the high rate of cleared infections (99.0%). Lowest vaccination rates were detected for HPV (0%) and Neisseria meningitidis (3.0%). CONCLUSIONS: Our data suggest that vaccination rates among PLWH are higher compared to the general German population. Implementation of EACS guidelines into daily routine though is not fully executed and the need for improving vaccination rates has to be emphasized. Centrally organized vaccination registers as well as electronic medical records could be helpful tools to detect a lack of vaccination coverage and send digital vaccination reminders particularly among risk groups.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium.

BACKGROUND: Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. METHODS: The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. RESULTS: 14 703 people were included in this study, of whom 7863 (53·5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1·27, 95% CI 1·17-1·38), raltegravir (1·37, 1·20-1·56), and tenofovir alafenamide (1·38, 1·22-1·35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2·10, 1·91-2·31 for underweight vs healthy weight) and Black ethnicity (1·61, 1·47-1·76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0·97, 0·96-0·98 per 100 cells per µL increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1·21, 95% CI 1·19-1·32) and tenofovir alafenamide without dolutegravir (1·33, 1·15-1·53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1·79, 1·52-2·11, and 1·70, 1·44-2·01, respectively). INTERPRETATION: Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment-Experienced People Living With Human Immunodeficiency Virus.

BACKGROUND: Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. METHODS: Antiretroviral treatment-experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012-1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. RESULTS: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7-24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8-38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5-8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9-6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72-1.19; P = .53). CONCLUSIONS: This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium.

OBJECTIVES: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. METHODS: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/µL. RESULTS: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04). CONCLUSION: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Circulating levels of PRO-C3 reflect liver fibrosis and liver function in HIV positive patients receiving modern cART.

BACKGROUND AND AIMS: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART. METHODS: 116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs. RESULTS: Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis. CONCLUSION: The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART.

Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study.

Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate.

Moderate endurance training (marathon-training) - effects on immunologic and metabolic parameters in HIV-infected patients: the 42 KM cologne project.

BACKGROUND: Improved treatment options of HIV have resulted in regular physical activities of many HIV-infected patients. However, data on effects of sports in HIV-patients are scarce. METHODS: 21 HIV-infected persons were monitored prospectively while preparing for a marathon run. Multiple parameters with regard to immunology, quality of life and metabolism were measured at 4 time points (at baseline 1 year before the marathon run, 3 and 6 months after beginning of training, and immediately before marathon). RESULTS: 13 out of 21 participants completed the marathon (12 male, 1 female; median age 42 years [27-50]; CD4 = 620/µl [146-1268]; 11 were on ART since 3.5 years [1-7]). 8 participants ceased training early. All reasons for stopping (besides one pre-existing metatarsal fracture) were not regarded as training-related (e.g. time limitation n = 3; newly diagnosed anal cancer n = 1; personal reasons/unknown n = 3). We observed a significant increase in absolute CD4-T-cells (620/µl [146-1268] vs. 745 [207-1647]; p = 0.001) with simultaneous decrease of CD4-T-cell apoptosis (53% [47-64] vs. 32% [14-42]); p < 0.01). No effects on viral load independent of ART occurred. Systolic blood pressure and cholesterol improved significantly, although moderate and normal at baseline (cholesterol 185 mg/dl [98-250] vs. 167 [106-222], p = 0.02; RRsys 125 mmHg [100-145] vs. 120 [100-140], p = 0.01). Blood count, liver enzymes, creatinine and CK remained unchanged. CONCLUSIONS: The results of this pilot study indicated improved metabolic and immunologic parameters in HIV-infected patients undergoing moderate endurance training. Although training effects or ART cannot be ultimately separated as underlying mechanisms, we conclude that marathon training is safe for HIV-infected patients and potentially improves general health. TRIAL REGISTRATION: DRKS00011592 (retrospectively registered on February 9th 2017).

Liver Fibrosis in HIV Patients Receiving a Modern cART: Which Factors Play a Role?

Liver-related death in human immunodeficiency virus (HIV)-infected individuals is about 10 times higher compared with the general population, and the prevalence of significant liver fibrosis in those with HIV approaches 15%. The present study aimed to assess risk factors for development of hepatic fibrosis in HIV patients receiving a modern combination anti-retroviral therapy (cART). This cross-sectional prospective study included 432 HIV patients, of which 68 (16%) patients were anti-hepatitis C virus (HCV) positive and 23 (5%) were HBsAg positive. Health trajectory including clinical characteristics and liver fibrosis stage assessed by transient elastography were collected at inclusion. Liver stiffness values >7.1 kPa were considered as significant fibrosis, while values >12.5 kPa were defined as severe fibrosis. Logistic regression and Cox regression uni- and multivariate analyses were performed to identify independent factors associated with liver fibrosis. Significant liver fibrosis was detected in 10% of HIV mono-infected, in 37% of HCV co-infected patients, and in 18% of hepatitis B virus co-infected patients. The presence of diabetes mellitus (odds ratio [OR] = 4.6) and FIB4 score (OR = 2.4) were independently associated with presence of significant fibrosis in the whole cohort. Similarly, diabetes mellitus (OR = 5.4), adiposity (OR = 4.6), and the FIB4 score (OR = 3.3) were independently associated with significant fibrosis in HIV mono-infected patients. Importantly, cumulative cART duration protected, whereas persistent HIV viral replication promoted the development of significant liver fibrosis along the duration of HIV infection. Our findings strongly indicate that besides known risk factors like metabolic disorders, HIV may also have a direct effect on fibrogenesis. Successful cART leading to complete suppression of HIV replication might protect from development of liver fibrosis.

Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort.

Overall survival (OS) of patients with acquired immunodeficiency syndrome (AIDS)-related Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) was analysed in the German AIDS-related-Lymphoma-Cohort-Study. Of 291 patients prospectively included between January 2005 and December 2012, 154 had DLBCL, 103 BL and 34 PBL. Two-year OS rates were similar between BL (69%) and DLBCL patients (63%) but lower for PBL patients (43%). Intermediate (Hazard ratio [HR] 4·1 95% confidence interval [CI] 1·98-8·49) or high (HR 4·92 95% CI 2·1-11·61) International Prognostic Index, bone marrow involvement (HR 1·69 95% CI 1·00-2·84) and PBL histology (HR 2·24 95% CI 1·24-4·03) were independent predictors of mortality.

Dose-intensive chemotherapy including rituximab is highly effective but toxic in human immunodeficiency virus-infected patients with Burkitt lymphoma/leukemia: parallel study of 81 patients.

The results of intensive immunochemotherapy were analyzed in human immunodeficiency virus (HIV)-related Burkitt lymphoma/leukemia (BLL) in two cohorts (Spain and Germany). Alternating cycles of chemotherapy were administered, with dose reductions for patients over 55 years. Eighty percent of patients achieved remission, 11% died during induction, 9% failed and 7% died in remission. Four-year overall survival (OS) and progression-free survival (PFS) probabilities were 72% (95% confidence interval [CI]: 62-82%) and 71% (95% CI: 61-81%). CD4 T-cell count < 200/µL and bone marrow involvement were associated with poor OS (hazard ratio [HR] 3.2 [1.2-8.3] and HR 2.7 [1.1-6.6]) and PFS (HR 3.5 [1.3-9.1] and HR 2.4 [1-5.7]), bone marrow involvement with poor disease-free survival (DFS) (HR 14.4 [1.7-119.7] and Eastern Cooperative Oncology Group (ECOG) score > 2 (odds ratio [OR] 11.9 [1.4-99.9]) with induction death. In HIV-related BLL, intensive immunochemotherapy was feasible and effective, but toxic. Prognostic factors were performance status, CD4 T-cell count and bone marrow involvement.

Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients.

BACKGROUND: Noncirrhotic portal hypertension (NCPH) is a rare but potentially life-threatening complication in patients with human immunodeficiency virus (HIV). Cases of NCPH have been reported in HIV-negative individuals as result of treatment with thiopurines for leukemia or inflammatory bowel disease. Exposure to didanosine, which is also a purine analogue, predisposes to NCPH in the HIV setting. However, it is unclear why NCPH only develops in a small subset of didanosine-treated patients. METHODS: A multicenter, case-control study was conducted to investigate the role of pharmacogenomics in NCPH in HIV patients with prior didanosine exposure. Three controls were chosen for each case, adjusted for sex, age, CD4 counts, plasma HIV-RNA, and site. Tagging 36 single-nucleotide polymorphisms (SNPs) at enzymes involved in the purine metabolism (inosine triphosphatase, 5'-nucleotidase cytosolic-II, purine nucleoside phosphorylase and xanthine oxidase) was performed using SNPlex microarray technology. RESULTS: Eighty individuals were examined; 22 with NCPH and 58 matched controls. Two SNPs at the 5'-nucleotidase gene were associated with NCPH: rs11191561 (48% CG/GG vs 17% CC; P=.003) and rs11598702 (40% CC/CT vs 9% TT; P=.003). SNPs at another 2 loci at the xanthine oxidase gene were also associated with NCPH: rs1429376 (71% AA vs 23% CC/AC; P=.015) and rs1594160 (71% AA vs 23% CC/AC; P=.015). There was a cumulative risk of NCPH for these 4 SNPs: 7%, 26%, 42%, 50%, and 100%, respectively, for 0, 1, 2, 3, or all SNPs (P=.001). CONCLUSIONS: SNPs at the 5'-nucleotidase and xanthine oxidase genes influence the risk of NCPH in HIV patients treated with didanosine.

Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study.

BACKGROUND: Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries. METHODS: We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per microL while ART naive. All pre-ART CD4 counts greater than 350 cells per microL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups--men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods. FINDINGS: Data were analysed for 40,830 patients contributing 80,682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1.30, 95% CI 1.06-1.58); 68 heterosexual people (2.94, 2.28-3.73); 203 injecting drug users (9.37, 8.13-10.75); and 30 in the other or unknown risk category (4.57, 3.09-6.53). Compared with CD4 counts of 350-499 cells per microL, death rate was lower in patients with counts of 500-699 cells per microL (adjusted rate ratio 0.77, 95% CI 0.61-0.95) and counts of 700 cells per microL (0.66, 0.52-0.85). INTERPRETATION: In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited. FUNDING: European Commission, FP6. European AIDS Treatment Network (NEAT). Project number LSHP-CT-2006-037570.

Massive hypercoagulable state despite full-dose anticoagulant treatment in a patient with occult malignancy: considerations concerning chemotherapy without definitive diagnosis.

A 55-year-old female patient presented with recurrent deep venous thrombosis and pulmonary embolism while on oral anticoagulant treatment using the vitamin K antagonist phenprocoumon. Hypercoagulable state was regarded to be paraneoplastic, but no underlying malignancy could be identified despite extensive screening for cancer, including gastroscopy and colonoscopy, a bone marrow biopsy, thoracoabdominal CT scans with subsequent biopsies of possibly malignant findings, octreotide scintigraphy, skeletal scintigraphy and gynaecological screening. In the course of her hospital stay she developed progressive right cardiac insufficiency due to the formation of new thromboses despite aggressive anticoagulant treatment and died of right-sided heart failure. The autopsy showed a poorly differentiated adenocarcinoma in the middle lobe of the right lung. In addition, pulmonary lymphangiosis carcinomatosa, pleural and pericardial carcinosis, and lymph node metastases and osteoblastic vertebral body metastases were shown.

Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin's disease.

Hodgkin's disease (HD) is the most common non-acquired immunodeficiency syndrome (AIDS)-defining malignancy in human immunodeficiency virus (HIV)-infected patients. We analysed the outcome of patients with HIV-associated HD (HIV-HD) with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and other prognostic factors. To evaluate the effects of several variables on overall survival (OS), Kaplan-Meier statistics and extended Cox regression analysis were performed. Response to HAART was used as a time-dependent variable and was defined as an increase of >0.1 x 10(9) CD4 cells/l and/or at least one viral load <500 copies/ml during the first 2 years following diagnosis of HIV-HD. Fifty-seven patients with HIV-HD diagnosed between 1990 and 2002 were included in the study. In the Cox model, the only factors independently associated with OS were HAART response [relative hazard (RH) 0.19; 95% confidence interval (CI) 0.06-0.60], complete remission (RH 0.30, 95% CI 0.13-0.72), and age