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Objectives: To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART)., Design: Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012., Methods: We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall-Wallis, analysis of variance and Fisher's exact tests were used to evaluate between-group differences., Results: Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42-55%; P = 0.006), more likely to be on ART (100 vs. 55-68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54-58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA., Conclusion: RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.

In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.0%) and was well tolerated through week 48. Four patients discontinued study drug due to an adverse event and none due to proximal renal tubulopathy. As expected, decreases in CrCl were noted as early as week 2, after which they stabilized. The renal safety profile of STB in patients from this study is consistent with the long-term experience in a large number of patients with CrCl ≥70 mL/min.

Background: Cobicistat (COBI) is a pharmacoenhancer that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV)., Objective: To evaluate the efficacy and safety of switching ritonavir (RTV) to COBI in patients with creatinine clearance (CrCl) 50 to 89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted ATV or DRV. Other components of the regimen remained unchanged., Methods: A phase 3, non-comparative, open-label clinical trial., Results: Seventy-three patients were enrolled. At week 48, 82% maintained virologic suppression. No emergent resistance developed. Serious adverse events (AEs) occurred in 7%, and study drug discontinuation due to AEs occurred in 10% (7 patients). There were 2 renal discontinuations and no cases of proximal renal tubulopathy. Small reductions in CrCl (median [IQR]) were observed as early as week 2, after which they were nonprogressive through week 48 (-3.8 [-9 to 0.8]). Changes in CrCl by baseline CrCl (< 70 vs ≥ 70) were -1.1 [-6.5 to 6.3] versus -6.6 [-12.4 to -0.7], respectively., Conclusions: In HIV-1-infected patients with CrCl 50 to 89 mL/min switching from RTV to COBI, COBI-boosted PIs in combination with 2 nucleos(t)ide reverse transcriptase inhibitors were well-tolerated and effective in maintaining virologic suppression. The renal safety profile of COBI in this study was consistent with the long-term data in patients without renal impairment from the phase 3 studies of COBI-containing regimens.

End-stage kidney disease (ESKD) is a major complication of HIV infection. We observed a 3.8-fold increase in ESKD prevalence among black patients in the UK CHIC cohort during the 12-year study period. As of 2005, 107 patients had an ESKD diagnosis, 69 of whom (64%) were considered suitable for kidney transplantation (KT) and 34 (32%) had received a KT. Survival was similar for KT recipients and those awaiting KT (85% and 89% at 5 years, respectively; P = 0.53). Our results endorse the use of KT to manage ESKD in HIV-positive patients.

Background: Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy., Methods: Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression., Results: We observed declines in the eGFR during TDF exposure (mean slopes, -15.7 mL/minute/1.73 m(2)/year [95% confidence interval {CI}, -20.5 to -10.9] during the first 3 months and -3.1 mL/minute/1.73 m(2)/year [95% CI, -4.6 to -1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m(2)/year [95% CI, 8.9-16.1] during the first 3 months and 0.8 mL/minute/1.73 m(2)/year [95% CI, .1-1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy., Conclusions: This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Objectives: We investigated whether age modified associations between markers of HIV progression, CD4 T lymphocyte count and HIV RNA viral load (VL), and the following markers of metabolic function: albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC)., Methods: A retrospective analysis of data from the United Kingdom Collaborative HIV Cohort was carried out. Analyses were limited to antiretroviral-naïve subjects to focus on the impact of HIV disease itself. A total of 16670 subjects were included in the analysis. Multilevel linear regression models assessed associations between CD4 count/VL and each of the outcomes. Statistical tests for interactions assessed whether associations differed among age groups., Results: After adjustment for gender and ethnicity, there was evidence that lower CD4 count and higher VL were associated with lower TC, LDL-C, haemoglobin and albumin concentrations but higher triglyceride concentrations. Age modified associations between CD4 count and albumin (P < 0.001) and haemoglobin (P = 0.001), but not between CD4 count and HDL-C, LDL-C and TC, or VL and any outcome. Among participants aged < 30, 30-50 and > 50 years, a 50 cells/μL lower CD4 count correlated with a 2.4 [95% confidence interval (CI) 1.7-3.0], 3.6 (95% CI 3.2-4.0) and 5.1 (95% CI 4.0-6.1) g/L lower haemoglobin concentration and a 0.09 (95% CI 0.07-0.11), 0.12 (95% CI 0.11-0.13) and 0.16 (95% CI 0.13-0.19) g/L lower albumin concentration, respectively., Conclusions: We present evidence that age modifies associations between CD4 count and plasma albumin and haemoglobin levels. A given reduction in CD4 count was associated with a greater reduction in haemoglobin and albumin concentrations among older people living with HIV. These findings increase our understanding of how the metabolic impact of HIV is influenced by age., (© 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Assessment of renal function in HIV-positive patients is of increasing importance in the context of ageing and associated comorbidities. Exposure to nephrotoxic medications is widespread, and several commonly used antiretroviral drugs have nephrotoxic potential. Moreover, specific antiretrovirals inhibit renal tubular transporters resulting in the potential for drug-drug interactions as well as increases in serum creatinine concentrations, which affect estimates of glomerular filtration rate in the absence of changes in actual glomerular filtration rate. This review explores the effects of antiretroviral therapy on the kidney and offers an understanding of mechanisms that lead to apparent and real changes in renal function.

Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature. We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB in Eastern Europe between 2004 and 2006 to 89 patients whose Mycobacterium tuberculosis isolates were susceptible to isoniazid and rifampicin. Patients with HIV and MDR TB were young and predominantly male with high rates of intravenous drug use, imprisonment and hepatitis C co-infection. Eighty-four per cent of patients with MDR TB had no history of previous TB drug exposure suggesting that the majority of MDR TB resulted from transmission of drug-resistant M. tuberculosis. The use of non-standardized tuberculosis treatment was common, and the use of antiretroviral therapy infrequent. Compared to those with susceptible tuberculosis, patients with MDR TB were less likely to achieve cure or complete tuberculosis treatment (21.8% vs. 62.9%, p < 0.0001), and they were more likely to die (65.5% vs. 27.0%, p < 0.0001). Our study documents suboptimal management and poor outcomes in HIV positive patients with MDR TB. Implementation of WHO guidelines, rapid TB diagnostics and TB drug susceptibility testing for all patients remain a priority in this region., (Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection.

Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.

HIV-positive patients are at increased risk of end-stage kidney disease (ESKD). Kidney transplantation (KT) is an established treatment modality for ESKD in the general population. Recent data have confirmed the feasibility of kidney transplantation in HIV-positive patients, and kidney transplantation is increasingly offered to ESKD patients with well-controlled HIV infection. We report clinical outcomes in a national cohort study of kidney transplantation in HIV-positive patients. In all, 35 HIV-positive KT recipients who had undergone KT up to December 2010 (66% male, 74% black ethnicity) were identified; the median CD4 cell count was 366, all had undetectable HIV RNA levels at kidney transplantation, and 44% received a kidney from a live donor. Patient survival at 1 and 3 years was 91.3%, and graft survival 91.3% and 84.7%, respectively. At one-year post-kidney transplantation, the cumulative incidence of acute rejection was 48%, and the median (IQR) eGFR was 64 (46, 78) mL/min/1.73 m(2). Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. Our study corroborates the feasibility of kidney transplantation in HIV-positive patients. The high rates of acute rejection suggest that the optimal immune suppression strategy in this population remains to be refined.

Human immunodeficiency virus (HIV) therapy has evolved over the last 20 years from mono-drug therapy given five times daily to regimens consisting of three or four drugs combined in a single-tablet dosed once daily. To allow once-daily administration, several drugs require pharmacokinetic boosting by a concomitantly administered P-glycoprotein and cytochrome P450 inhibitor such as ritonavir. The availability of cobicistat provides an alternative to ritonavir to those who are intolerant to this drug, and the opportunity for co-formulated single-tablet regimens consisting of tenofovir/emtricitabine, cobicistat and elvitegravir, atazanavir or darunavir. The cobicistat/elvitegravir-based regimen is well tolerated and patients achieved high rates of HIV RNA suppression in clinical trials. Cobicistat inhibits renal tubular secretion of creatinine, resulting in increased serum creatinine concentrations and reduced estimated glomerular filtration rate, with a new set point reached after 4 weeks. Treatment limiting renal toxicity with cobicistat/elvitegravir and tenofovir disoproxil fumarate is infrequent and may be further reduced when cobicistat is co-formulated with tenofovir alafenamide fumarate, a novel formation of tenofovir currently undergoing clinical trials.

Objectives: To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir., Methods: Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list., Results: Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84-3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience., Conclusions: Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

Objectives: To assess health care utilisation for patients co-infected with TB and HIV (TB-HIV), and to develop a weighted health care index (HCI) score based on commonly used interventions and compare it with patient outcome., Methods: A total of 1061 HIV patients diagnosed with TB in four regions, Central/Northern, Southern and Eastern Europe and Argentina, between January 2004 and December 2006 were enrolled in the TB-HIV study. A weighted HCI score (range 0-5), based on independent prognostic factors identified in multivariable Cox models and the final score, included performance of TB drug susceptibility testing (DST), an initial TB regimen containing a rifamycin, isoniazid and pyrazinamide, and start of combination antiretroviral treatment (cART)., Results: The mean HCI score was highest in Central/Northern Europe (3.2, 95%CI 3.1-3.3) and lowest in Eastern Europe (1.6, 95%CI 1.5-1.7). The cumulative probability of death 1 year after TB diagnosis decreased from 39% (95%CI 31-48) among patients with an HCI score of 0, to 9% (95%CI 6-13) among those with a score of ≥4. In an adjusted Cox model, a 1-unit increase in the HCI score was associated with 27% reduced mortality (relative hazard 0.73, 95%CI 0.64-0.84)., Conclusions: Our results suggest that DST, standard anti-tuberculosis treatment and early cART may improve outcome for TB-HIV patients. The proposed HCI score provides a tool for future research and monitoring of the management of TB-HIV patients. The highest HCI score may serve as a benchmark to assess TB-HIV management, encouraging continuous health care improvement.

Background: HIV positive patients are at risk of infectious and non-infectious complications that may necessitate intensive care unit (ICU) admission. While the characteristics of patients requiring ICU admission have been described previously, these studies did not include information on the denominator population from which these cases arose., Methods: We conducted an observational cohort study of ICU admissions among 2751 HIV positive patients attending King's College Hospital, South London, UK. Poisson regression models were used to identify factors associated with ICU admission., Results: The overall incidence rate of ICU admission was 1.0 [95% CI 0.8, 1.2] per 100 person-years of follow up, and particularly high early (during the first 3 months) following HIV diagnosis (12.4 [8.7, 17.3] per 100 person-years compared to 0.37 [0.27, 0.50] per 100 person-years thereafter; incidence rate ratio 33.5 [23.4, 48.1], p < 0.001). In time-updated analyses, AIDS and current CD4 cell counts of less than 200 cells/mm3 were associated with an increased incidence of ICU admission while receipt of combination antiretroviral therapy (cART) was associated with a reduced incidence of ICU admission. Late HIV diagnosis (initial CD4 cell count <350 or AIDS within 3 months of HIV diagnosis) applied to 81% of patients who were first diagnosed HIV positive during the study period and who required ICU admission. Late HIV diagnosis was significantly associated with ICU admission in the first 3 months following HIV diagnosis (adjusted incidence rate ratio 8.72, 95% CI 2.76, 27.5)., Conclusions: Late HIV diagnosis was a major risk factor for early ICU admission in our cohort. Earlier HIV diagnosis allowing cART initiation at CD4 cell counts of 350 cells/mm3 is likely to have a significant impact on the need for ICU care.

Background: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality., Methods and Findings: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43)., Conclusions: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

Objectives: The study aimed at describing characteristics and outcome of tuberculous meningitis (TBM) in HIV-positive patients and comparing these parameters with those of extrapulmonary TB (TBEP) and pulmonary TB (TBP)., Methods: Kaplan-Meier estimation and Poisson regression models were used to assess the mortality following TB diagnosis and to evaluate potential prognostic factors for the 3 groups of TB patients separately., Results: A total of 100 patients with TBM, 601 with TBEP, and 371 TBP were included. Patients with TBM had lower CD4 cell counts and only 17.0% received antiretroviral therapy (ART) at TB diagnosis. The cumulative probability of death at 12 months following TB was 51.2% for TBM (95% CI 41.4-61.6%), 12.3% for TBP (8.9-15.7%), and 19.4% for TBEP (16.1-22.6) (P<0.0001; log-rank test). For TBM, factors associated with a poorer prognosis were not being on ART (adjusted incidence rate ratio (aIRR) 4.00 (1.72-9.09), a prior AIDS diagnosis (aIRR=4.82 (2.61-8.92)), and receiving care in Eastern Europe (aIRR=5.41 (2.58-11.34)))., Conclusions: TBM among HIV-positive patients was associated with a high mortality rate, especially for patients from Eastern Europe and patients with advanced HIV-infection, which urgently calls for public health interventions to improve both TB and HIV aspects of patient management.

Background: Chronic kidney disease is a risk factor for coronary heart disease (CHD). The association between renal impairment and CHD in HIV-positive patients remains poorly described., Objective: To describe the CHD incidence in a cohort of HIV-positive patients and to examine the relationship between reduced estimated glomerular filtration rate (eGFR) and incident CHD., Methods: We studied 7,828 HIV-positive patients who were followed up at 3 South London clinics between January 2004 and December 2009. CHD events were identified from electronic records and through elevated troponin levels. Multivariate Poisson regression analysis was used to identify factors associated with CHD among HIV-positive men., Results: The incidence of CHD among men was 1.2 (95% CI, 0.8-1.8) per 1,000 person-years of follow-up, with 28 patients (0.4%) having experienced 32 CHD events. In adjusted analyses, older age (incidence rate ratios [IRR], 2.81; 95% CI, 1.51-5.25) and hepatitis C virus (HCV) status (IRR, 3.94; 95% CI, 1.00-15.5) were significantly associated with CHD. Although eGFR as a continuous variable was not associated with CHD, an eGFR <75 mL/min remained associated with incident CHD (IRR, 4.30; 95% CI, 1.33-14.5) after adjustment for age. No association between CHD and abacavir exposure was observed (IRR, 0.94; 95% CI, 0.30-2.99)., Conclusions: The incidence of CHD in this ethnically diverse cohort was low. Our data suggest that impaired renal function identifies patients at increased risk of CHD events in whom management of traditional CHD risk factors should be prioritized.

Background: Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression., Study Design: Observational cohort study., Setting & Participants: 7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients., Predictor: Baseline estimated glomerular filtration rate (eGFR)., Outcomes: Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m(2) for >3 months) in Cox proportional hazards and competing-risk regression models., Results: Median age at baseline was 34 (25th-75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/μL, and median eGFR was 100 (25th-75th percentile, 87-112) mL/min/1.73 m(2). Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4-5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m(2) remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m(2) was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m(2) and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m(2)., Limitations: The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria., Conclusions: Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients., Methods: In a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI)., Results: Proteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR., Conclusions: In HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.

Context: Therapies to decrease immune activation might be of benefit in slowing HIV disease progression., Objective: To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline., Design, Setting, and Patients: Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL., Intervention: Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks., Main Outcome Measures: The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models., Results: There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03)., Conclusion: Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication., Trial Registration: isrctn.org Identifier: ISRCTN30019040.

Background: Renal dysfunction is common in HIV-positive patients, and guidelines suggest regular monitoring of renal function with estimated glomerular filtration rate (eGFR) and urinalysis. It is unknown whether Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) or Modification of Diet in Renal Disease (MDRD) provide better estimates of glomerular filtration rate (GFR) in this population., Methods: We compared the CKD-EPI and MDRD equations to estimate GFR at baseline in 20,132 HIV-positive individuals in the UK CHIC cohort. Kappa statistics and Bland-Altman plots were used to assess agreement between the two estimates and Kaplan-Meier plots and Cox regression analysis to describe mortality patterns., Results: At baseline, median eGFR was 100 (87, 112) (CKD-EPI) and 94 (83, 108) (MDRD) (mL/min/1.73 m(2)). Good overall agreement between CKD-EPI- and MDRD-defined eGFR bands was observed (Kappa = 0.71, 95% confidence interval: 0.70-0.72). Of the 367 patients with eGFR MDRD 30-59, 57 (15.5%) were categorized as eGFR 60-89 by CKD-EPI. After adjustment for covariates, eGFR <60 (CKD-EPI), eGFR <30 (MDRD) and eGFR ≥105 (both formulae) were significantly associated with an increased risk of death. Mortality in patients classified as having eGFR 60-89 by CKD-EPI and eGFR 30-59 by MDRD more closely resembled mortality of patients who had eGFR 60-89 by both formulae., Conclusions: MDRD and CKD-EPI equations showed a high degree of agreement in stratifying patients by baseline eGFR. CKD-EPI estimates of GFR <60 at baseline are more strongly associated with mortality than MDRD estimates of GFR <60, supporting the concept that MDRD may have overestimated the severity of renal impairment in these patients. Our findings support the use of CKD-EPI in HIV-positive individuals.

Acute renal failure and chronic kidney disease are more common in HIV-infected patients compared with the general population. Several studies have shown age to be a risk factor for HIV-associated kidney disease. The improved life expectancy of HIV-infected patients as a result of widespread use of antiretroviral therapy has resulted in progressive aging of HIV cohorts in the developed world, and an increased burden of cardiovascular and kidney disease. Consequently, HIV care increasingly needs to incorporate strategies to detect and manage these non-infectious co-morbidities.

Purpose of Review: Renal disease is increasingly common as life expectancy of HIV-infected persons continues to improve. Several biomarkers are available for monitoring renal function, although no consensus exists on how best to apply these tools in HIV infection. This review describes recent findings for the more common renal biomarkers., Recent Findings: Although widely used in clinical practice, creatinine-based estimates of glomerular filtration rate have not been validated in HIV infection. Serum cystatin C has been proposed as a more sensitive marker of renal dysfunction in HIV infection, although it may also reflect systemic inflammation. Screening for proteinuria and albuminuria allows identification of patients at higher risk of kidney disease and other adverse outcomes. Fanconi syndrome, which has been associated with tenofovir use, is associated with severe tubular proteinuria, and several low molecular weight proteins, including retinol-binding protein, β2-microglobulin, and neutrophil gelatinase-associated lipocalin have been studied as markers of tubular dysfunction. Studies have reported a high prevalence of subclinical proximal tubular dysfunction in patients receiving antiretroviral therapy., Summary: Future studies are needed to determine the optimal biomarkers for the detection and monitoring of renal disease in HIV.

Objective: To identify risk factors for acute renal failure (ARF) in HIV-infected patients., Design: Observational cohort study of HIV-infected patients attending a South London HIV centre between January 1999 and December 2008., Methods: ARF was defined as a transient, more than 40% reduction in renal function as assessed by estimated glomerular filtration rate. Multivariate Poisson regression analysis was used to identify baseline and time-updated factors associated with ARF., Results: The incidence of ARF was 2.8 (95% confidence interval 2.41-3.24) episodes per 100 person-years. We observed a stepwise increase in ARF incidence with time accrued at lower CD4 cell count and at lower estimated glomerular filtration rate, with adjusted incidence rate ratios of 1 (reference), 1.56 (0.97-2.48), 2.08 (1.11-3.91), 6.38 (3.18-12.78) and 10.29 (5.11-20.98) for CD4 cell counts of more than 350, 201-350, 101-200, 51-100 and of 50/microl or less, and 1 (reference), 1.46 (0.86-2.51), 4.19 (2.37-7.42) and 27.00 (16.13-44.95) for estimated glomerular filtration rate more than 90, 75-89, 60-74 and less than 60 ml/min, respectively. Ethnicity, hepatitis B or C coinfection, exposure to combination antiretroviral therapy with or without indinavir, tenofovir or atazanavir and HIV viraemia were not associated with ARF., Conclusion: Current levels of immunodeficiency and renal function were independent predictors of HIV-associated ARF.

Background: Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies, yet few studies have comprehensively compared their safety profiles., Methods: Forty-eight-week data are presented from this multicenter, randomized, open-label study comparing the safety profiles of abacavir/lamivudine and tenofovir/emtricitabine, both administered with efavirenz, in HLA-B*5701-negative HIV-1-infected adults., Results: Three hundred eighty-five subjects were enrolled in the study. The overall rate of withdrawal was high (28%). Changes in estimated glomerular filtration rate from baseline were similar between arms [difference 0.953 mL.min.1.73 m (95% confidence interval: -1.445 to 3.351), P = 0.435]. Urinary excretion of retinol-binding protein and beta-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm (+50%; +24%) compared with the abacavir/lamivudine arm (no change; -47%) (P < 0.0001). A lower proportion achieved viral load <50 copies per milliliter in the abacavir/lamivudine arm (114 of 192, 59%) compared with the tenofovir/emtricitabine arm (137 of 193, 71%) [difference 11.6% (95% confidence interval: 2.2 to 21.1)]. The overall virological failure rate was low. The adverse event rate was similar between arms (except drug hypersensitivity, reported more in the abacavir/lamivudine arm)., Conclusions: The study showed no difference in estimated glomerular filtration rate between the arms, however, increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm, the long-term consequence of which is unclear. A significant difference in efficacy favoring tenofovir/emtricitabine was observed.

Objective(s): To identify factors (including exposure to specific antiretroviral drugs) associated with severe vitamin D deficiency (VDD) in HIV-infected individuals and to explore the effects of severe VDD and antiretroviral drug exposure on serum alkaline phosphatase (ALP) as surrogate marker of bone turnover., Design: Cross-sectional survey of vitamin D status among HIV-infected patients attending for routine clinical care at a large London HIV clinic., Methods: Severe VDD was defined as 25(OH)D levels of less than 10 microg/l (<25 nmol/l). Multivariate logistic regression analysis was used to identify factors associated with severe VDD and upper quartile ALP levels., Results: Vitamin D levels were measured in 1077 patients and found to be suboptimal in 91%. One-third of patients had severe VDD. Black ethnicity, sampling in winter, nadir CD4 cell count less than 200 cells/microl, and exposure to combination antiretroviral therapy were associated with severe VDD. In analyses restricted to patients on combination antiretroviral therapy, current efavirenz use was significantly associated with severe VDD [adjusted odds ratio 2.0 (95% confidence interval 1.5-2.7)]. Current tenofovir [adjusted odds ratio 3.5 (95% confidence interval 2.3-5.2)] and efavirenz use [adjusted odds ratio 1.6 (95% confidence interval 1.02-2.4)], but not severe VDD [odds ratio 1.1 (0.8-1.5)], were associated with increased bone turnover (upper quartile ALP)., Conclusion: Efavirenz was associated with severe VDD, a condition associated with multiple adverse health outcomes, and efavirenz and tenofovir with increased ALP. The clinical significance of these findings requires further investigation, given the widespread use of efavirenz and tenofovir in first-line combination antiretroviral therapy.

Background and Objectives: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina., Methods: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models., Results: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/microl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe., Conclusion: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention.

Objective: To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom., Design: Observational cohort study., Setting: Seven leading HIV centres and affiliated renal clinics in the United Kingdom., Participants: A total of 21 951 patients in whom renal function was measured., Main Outcome Measure: Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT)., Results: Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998-1999 to 0.92% in 2006-2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year., Conclusion: The prevalence of HIV/ESRF increased during the HAART era to reach nearly 1% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stem the rising trend of HIV/ESRF.

Cerebral toxoplasmosis can occur outside the setting of advanced HIV immunodeficiency or drug-induced immunosuppression. A case of cerebral toxoplasmosis is reported in a previously healthy 41-year-old man who was found to have a genetic defect in CD40 ligand, resulting in the X linked hyper-IgM syndrome despite normal surface protein expression on flow cytometry. This highlights the fact that primary immunodeficiencies can first present late in life with a relatively mild phenotype and should be considered in the differential diagnosis of opportunistic infections in non-HIV infected patients; in addition, normal protein expression does not necessarily rule out hypomorphic mutations.

Background: The clinical epidemiology of acute renal failure (ARF) in human immunodeficiency virus (HIV)-infected patients remains poorly defined., Methods: We conducted a retrospective analysis of patients who developed ARF while attending King's College Hospital (London, United Kingdom) during January 1998-December 2005. Serum creatinine level and estimated glomerular filtration rate were used to identify ARF. ARF episodes were classified as early onset if they occurred <3 months after initiation of HIV care and as late onset if they occurred > or =3 months after initiation of HIV care., Results: During the study period, 130 (5.7%) of 2274 patients developed 144 episodes of ARF. The incidences of early-onset and late-onset ARF were 19.3 episodes per 100 person-years (95% confidence interval [CI], 15.4-24.1 episodes per 100 person-years) and 1.1 episodes per 100 person-years (95% CI, 0.83-1.49 episodes per 100 person-years), respectively (rate ratio, 17.4; P<0.001). In multivariate analysis, nadir CD4 T cell count <100 x 10(9) cells/L (odds ratio [OR], 6.7; 95% CI, 2.5-18.3) and acquired immunodeficiency syndrome (OR, 6.7; 95% CI, 3.4-13.3) were associated with early-onset ARF, whereas injection drug use (OR, 4.8; 95% CI, 1.3-17.7), hepatitis C virus coinfection (OR, 3.4; 95% CI, 1.3-8.6), and nadir CD4 T cell count <100 x 10(9) cells/L (OR, 5.8; 95% CI, 2.5-13.4) were associated with late-onset ARF., Conclusions: ARF was common and was associated with advanced immunodeficiency. The incidence of ARF decreased >10-fold in patients who had received HIV care for > or =3 months.

Background: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease., Methods: We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified., Results: From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001)., Conclusions: Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.

Objective: We aimed to see if structured treatment interruption (STI) could be supported safely with the use of two cycles of IL-2 (4.5 MIU q12h subcutaneously 5 days) before STI to prolong the time before therapy restarted., Methods: Subjects were randomly allocated to either A - continuous ART; B - continue for 9 weeks, then STI; restart with the same ART when the CD4 count falls below 200 cells; or C - two cycles of IL-2, 8 weeks apart, while still on ART; at week 9 stop ART and use a new cycle of IL-2 alone whenever the CD4 count falls < 300 cells. Patients were followed until week 105., Results: 86 mostly white middle aged homosexual men with a baseline median CD4 count of 754 cells/ml (range 240-1400) and a nadir CD4 count of 268 cells/ml (range 62-822) enrolled. By 96 weeks there was a 66% probability of having restarted ART in arm B compared with 34% in arm C (p = 0.002; log rank test). New drugs were used in 60% in arm A, 57% in arm B and 45% in arm C. 4 subjects had a dose modification in the first cycle due to toxicity with 2 interrupting. There were 39 SAEs with 21 in arm C. There were no deaths., Conclusions: The primary aim of the trial was to gain experience in using IL-2. IL-2 delayed restarting drugs and fewer new drugs were used.

Kidney disease is an important complication of HIV infection. Antiretroviral therapy has dramatically improved the life expectancy of HIV-infected patients with end-stage renal disease. Renal replacement therapy, including kidney transplantation, should be offered to HIV-positive patients.

With the advent of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections has declined substantially, and cardiovascular, liver, and renal diseases have emerged as major causes of morbidity and mortality in individuals with human immunodeficiency virus (HIV). Acute renal failure is common in HIV-infected patients and is associated with acute infection and medication-related nephrotoxicity. HIV-associated nephropathy is the most common cause of chronic kidney disease in HIV-positive African American populations and may respond to HAART. Other important HIV-associated renal diseases include HIV immune complex kidney diseases and thrombotic microangiopathy. The increasing importance of non-HIV-associated diseases, such as diabetes mellitus, hypertension, and vascular disease, to the burden of chronic kidney disease has been recognized, focusing attention on prevention and control of these diseases in HIV-positive individuals. HIV-positive individuals who experience progression to end-stage renal disease and who have undetectable HIV-1 viral loads while receiving HAART should be evaluated for renal transplant. Emerging evidence suggests that HIV-positive individuals may have graft and patient survival comparable to HIV-negative individuals. Several studies suggest that HIV-1 can potentially infect renal cells, and HIV transgenic mice have clarified the roles of a number of HIV proteins in the pathogenesis of HIV-associated renal disease. Host factors may modify disease expression at the level of cytokine networks and the renal microvasculature and contribute to the pathogenic effects of HIV-1 infection on the kidney.

Multidrug-resistant tuberculosis (MDR-TB) poses a serious threat to global public health. The mutations responsible for drug resistance in Mycobacterium tuberculosis have been identified, but what impact these mutations have on bacterial fitness is controversial. We analyzed 3 MDR strains of M. tuberculosis obtained from human immunodeficiency virus-negative patients with chronic pulmonary TB. One of these strains harbored a chromosomal deletion encompassing 15 open reading frames. Genes deleted in this strain included acr1, which encodes the virulence factor alpha-crystallin (Acr) 1, a protein that has been reported to be essential for M. tuberculosis replication in macrophages. We found that all 3 MDR isolates, including the acr1-deficient strain, replicated in cultured murine and human macrophages with the same kinetics as H37Rv, a virulent laboratory strain. These observations challenge the prevailing view that MDR bacteria are less fit than drug-susceptible bacteria and indicate that Acr1 is dispensable for bacterial growth in the human lung.

The role of tumor necrosis factor-alpha (TNF-alpha) in controlling growth of Mycobacterium tuberculosis in murine peritoneal macrophages infected in vitro was studied. TNF-alpha was shown to be required but not sufficient, and the amount of TNF-alpha produced by the infected cells did not correlate with the extent of growth control. In this system, TNF-alpha-dependent control of growth of the avirulent strain H37Ra was independent of inducible nitric oxide synthase (iNOS) and interferon-gamma (IFN-gamma), as shown by the infection of macrophages from selected gene-disrupted mice. TNF-alpha-mediated bacteriostasis of H37Ra in the infected macrophages was associated with increased expression of selected Th1-type cytokines and chemokines. In contrast, growth of the virulent strain H37Rv in macrophages involved upregulation by infected cells of Th2-type cytokines, including interleukin-5 (IL-5), IL-10, and IL-13. Taken together, these results suggest that the particular nature of macrophage activation and the cytokine and chemokine response to infection with different M. tuberculosis strains determine the ability of the cells to control the growth of the intracellular bacilli.

Current recommendations state that antiretroviral therapy (ART) should be commenced before the onset of severe HIV-associated immune deficiency and the development of AIDS-defining infections or malignancies. However, many patients only present and are diagnosed with HIV infection when they already have advanced disease. The optimal treatment for patients with advanced HIV disease remains to be defined. Key management questions include whether the virological and immunological responses to ART are comparable to those seen in patients with less advanced disease; whether the efficacy of different antiretroviral (ARV) regimens differs in patients with advanced disease; and whether there is an increased risk of drug toxicity and the immune reconstitution inflammatory syndrome.

Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem because treatment is complicated, cure rates are well below those for drug-susceptible tuberculosis (TB), and patients may remain infectious for months or years, despite receiving the best available therapy. To gain a better understanding of MDR-TB, we characterized serial isolates recovered from 13 human immunodeficiency virus-negative patients with MDR-TB, by use of IS6110 restriction fragment-length polymorphism analysis, spacer oligonucleotide genotyping (i.e., "spoligotyping"), and sequencing of rpoB, katG, mabA-inhA (including promoter), pncA, embB, rpsL, rrs, and gyrA. For all 13 patients, chronic MDR-TB was caused by a single strain of Mycobacterium tuberculosis; 8 (62%) of the 13 strains identified as the cause of MDR-TB belonged to the W-Beijing family. The sputum-derived isolates of 4 (31%) of the 13 patients had acquired additional drug-resistance mutations during the study. In these 4 patients, heterogeneous populations of bacilli with different resistance mutations, as well as mixtures of drug-susceptible and drug-resistant genotypes, were observed. This genetic heterogeneity may require treatment targeted at both drug-resistant and drug-susceptible phenotypes.

Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated.

Pathogenetic processes that facilitate the entry, replication, and persistence of Mycobacterium tuberculosis (MTB) in the mammalian host likely include the regulated expression of specific sets of genes at different stages of infection. Identification of genes that are differentially expressed in vivo would provide insights into host-pathogen interactions in tuberculosis (TB); this approach might be particularly valuable for the study of human TB, where experimental opportunities are limited. In this study, the levels of selected MTB mRNAs were quantified in vitro in axenic culture, in vivo in the lungs of mice, and in lung specimens obtained from TB patients with active disease. We report the differential expression of MTB mRNAs associated with iron limitation, alternative carbon metabolism, and cellular hypoxia, conditions that are thought to exist within the granulomatous lesions of TB, in the lungs of wild-type C57BL/6 mice as compared with bacteria grown in vitro. Analysis of the same set of mRNAs in lung specimens obtained from TB patients revealed differences in MTB gene expression in humans as compared with mice.

Mortality and HIV prevalence rose concordantly at Brooklyn Chest Hospital from 1998 to 2001. Death and unconfirmed tuberculosis (TB) (15% of adult admissions in a sample from 2000) were associated with HIV seropositivity. Excluding unconfirmed TB and shortening length of stay would increase the number of patients able to benefit from hospitalisation.

Objective: Evaluation of prognostic significance of the type of AIDS-defining illness (ADI) and performance status in a cohort of AIDS patients., Design, Setting, Subjects, Outcome Measures: A retrospective analysis of 280 patients with AIDS, as defined by the proposed World Health Organisation (WHO) clinical staging system, who attended two Cape Town-based HIV clinics between 1984 and 1997. Patients were stratified according to the type of initial ADI. Survival associated with each opportunistic event was determined by Kaplan-Meier analysis. Cox proportional hazard analysis was used to determine relative risk for death associated with three strata of ADI., Results: Median survival associated with various initial ADIs varied from less than 3 months (encephalopathy and wasting), to over 2 years (extrapulmonary tuberculosis and herpes simplex virus infection). This effect of ADI on outcome was most striking in patients with relatively preserved CD4 counts (CD4 > 50/microliter). A performance status score 4 predicted 50% mortality at 1 month, irrespective of co-morbidity., Conclusion: The type of ADI is an important determinant of survival, particularly in patients with preserved CD4 counts. The stratification of patients by type of ADI and performance status may be useful in the management of patients with advanced HIV infection in resource-limited environments.