Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery

We estimated the effect of initiating virologically suppressive antiretroviral therapy (ART) during acute HIV infection versus chronic HIV infection (AHI vs. CHI) on CD4/CD8 ratio normalization. A prospective clinical cohort study. We included patients initiating ART with AHI and CHI between 2000 and 2015 and compared time from ART initiation to the first normal CD4/CD8 ratio (defined as CD4/CD8 ≥1) using Kaplan-Meier curves and multivariable Cox proportional hazards models. Patient time was censored at virologic failure, lost to follow-up, or death. We also characterized CD4, CD8, and CD4/CD8 trajectories over the first 3 years of ART. The 1198 patients were 27% female and 60% African American, with a median age of 37 years (interquartile range 28-47) at ART initiation. The 83 AHI patients were more likely male, younger, and of white race, than CHI patients. After 2 years of suppressive ART, 70% of AHI patients achieved a normal CD4/CD8 ratio, compared to 6%-38% of CHI patients, with greater likelihood of normalization at higher baseline CD4 counts. Time to normalization was shortest among AHI patients, followed by CHI patients with higher baseline CD4. The adjusted hazard ratio for time to normalization for AHI patients compared to CHI patients with baseline CD4 >350 was 4.33 (95% CI: 3.16 to 5.93). Higher baseline CD4/CD8 ratio was also associated with time to normalization (adjusted hazard ratio 1.54; 1.46, 1.63, per 0.1 increase in ratio). Initiating ART during AHI at higher baseline CD4 cell counts and CD4/CD8 ratios was associated with shorter time to CD4/CD8 ratio normalization.

Antiretroviral Therapy and Tuberculosis: What's the Connection and What's the Way Forward?

To the Editors: INTRODUCTION People with HIV (PWH) have elevated risks for heart failure (HF),1,2 which can manifest during various stages of HIV infection. Among PWH, a lower nadir CD4 count (<200 cells/mm3) is associated with a higher HF risk.3 However, less is known regarding cardiac dysfunction in PWH with severe CD4 lymphopenia starting antiretroviral therapy (ART); such data are derived primarily from historical case series of AIDS cardiomyopathy and preceded detailed hemodynamic and tissue characterization on cardiac imaging.4–6 Of interest are PWH with immune reconstitution inflammatory syndrome (IRIS), who experience a dramatic increase in systemic and tissue inflammation after initiation of ART. Up to one-third of US PWH, and a larger proportion worldwide, present with CD4 counts <200 and are at a heightened risk for IRIS7; therefore, there is clinical relevance in determining factors underlying cardiac dysfunction in lymphopenic patients initiating ART. Given the dearth of modern data on cardiac function in PWH presenting with severe immunosuppression, we investigated associations of immunologic and inflammatory markers with cardiac function and intracardiac pressures in a cohort of PWH presenting with severe lymphopenia. METHODS Study Design We performed a nested study within a prospective cohort of PWH at the National Institute of Allergy and Infectious Diseases (NIAID) HIV clinic between January 1, 2007, and July 24, 2019. The cohort included patients from the following 2 clinical protocols: (1) Immune reconstitution syndrome in HIV-infected patients taking ART (IRIS, NCT00286767) and (2) positron emission tomography Imaging and Lymph Node Assessment of IRIS in People with AIDS (PANDORA, NCT02147405). Inclusion criteria included age ≥18 years, documented HIV infection, CD4 count <100 cells/µL, no previous ART, and willingness to start therapy. Exclusion criteria were pregnancy and active substance use. All study participants signed informed consent and were followed prospectively from ART initiation (week 0) to weeks 2, 4, 8, 12, 24, 36, and 48. ART regimens and initiation time were chosen according to local treatment guidelines and clinicians' preferences. The clinical team at the study site identified IRIS events as previously published.8,9 For this analysis, data elements derived from the IRIS and PANDORA studies were paired with echocardiographic data from the subset of IRIS and PANDORA participants who had clinically indicated echocardiography performed in the course of clinical care. The primary analyses focused on echocardiographic parameters after ART initiation and included participants from IRIS and PANDORA with echocardiography performed within 100 days after ART initiation. Secondarily, we investigated associations of pre-ART immune markers with pre-ART cardiac markers in participants from IRIS and PANDORA who had echocardiography performed within 14 days before initiating ART. Laboratory Evaluations Plasma HIV viral load, CD4, and CD8 T-cell counts were performed using standardized assays at enrollment (baseline/week 0—before ART), after ART initiation (week 2), and within 10 days of the first echo (up to 100 days post-ART). Batched cryopreserved plasma samples from participants at baseline and week 2 were tested using electrochemiluminescence (Meso Scale Discovery, Rockville, MD) for C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); enzyme-linked fluorescent assay on a VIDAS instrument (bioMerieux, Marcy-l'Etoile, France) for D-dimer levels; and enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) for soluble tissue factor and soluble CD14 (sCD14). Echocardiographic Measurements Left ventricular ejection fraction (LVEF), right ventricular systolic pressure (RVSP), diastolic mitral inflow velocities, left ventricular end diastolic dimension, and left atrial end systolic diameter were measured. RVSP is a validated correlate of pulmonary arterial pressure,10 which is a marker of cardiac congestion and worsening HF.11 For the primary analyses, we used the first available data after starting ART [median time to echo 18 days [interquartile range (IQR) 7, 42]. For secondary analyses, data were derived from the latest pre-ART echocardiogram. Statistical Analysis Wilcoxon rank-sum and Fischer exact tests were used to compare demographics, ART categories, echo parameters, immunologic markers, and inflammatory markers. We measured associations of immune cell markers at baseline, week 2, and at the time of first post-ART echo as well as inflammatory markers at baseline and week 2, with echo measures post-ART. Secondary analyses compared pre-ART laboratory markers and echocardiographic data. Correlations were measured using Pearson's correlation coefficients. To account for multiple testing of correlations, Bonferroni correction was used (significance threshold of P < 0.0007). For the between-group comparisons, P < 0.05 threshold was used. The co-primary echo end points measured were LVEF and RVSP, both of which were log transformed for the analyses. RESULTS There were 91 participants with echocardiography performed within 100 days after ART initiation, of a total of 270 total IRIS and PANDORA participants. Seventy-three participants in IRIS and PANDORA had echocardiography performed within 14 days before ART initiation and were eligible for secondary analyses. Of note, only 13 study participants had both pre-ART and post-ART echocardiography, precluding adequately powered longitudinal comparisons of pre-ART to post-ART changes in echocardiographic parameters. The mean age of the group analyzed for primary analyses (N = 91) was 40.7 ± 11.4 years, 59% were men, and 75% were non-Hispanic Blacks. The baseline median CD4 count was 19 T cells/mm3 (IQR, 8–44), and the median viral load was 193,184 copies/mL (IQR, 88,911–456,875). ART class prevalence was as follows: 53% on nonnucleoside reverse transcriptase inhibitors, 32% on protease inhibitors, and 56% on integrase inhibitors. Thirty-one of the included patients (34.1%) developed IRIS, 19% of the overall cohort had clinical HF at baseline, 13% had Kaposi sarcoma, 7% had Cryptococcus, 12% had active tuberculosis, and 33% had pneumocystis pneumonia. Patients with vs. without IRIS had no differences in demographics, baseline HF, ART type, or opportunistic infections (Table 1). There was no difference in echo parameters or immune cell counts and viral load at baseline, week 2, or time of echo. Patients with IRIS had higher baseline levels of D-dimer and TNF-α and higher levels of D-dimer, TNF-α, CRP, and IL-6 at 2 weeks (Table 1). Of the 31 patients, 7 patients (22.6%) in the IRIS group had adjudicated HF vs. 10 of the 60 patients in the non-IRIS group (16.7%; P = 0.69). Patients with vs. without baseline HF had no significant demographic differences and no difference in baseline immune cell counts or viral load but had higher baseline IL-6 levels [median = 4.3 pg/mL (IQR, 3.6–8.5)] compared with those without {median = 2.4 pg/mL [(IQR, 1.7–4.6), P = 0.035]}. TABLE 1. - Associations of Demographics, Clinical Variables, and Laboratory Markers With Cardiac Function and the Presence of IRIS Right Ventricle Systolic Pressureb Left Ventricle Ejection Fractionb IRIS absent (n = 60) IRIS Present (n = 31) P Statistica P Statistica P Age, yr (mean ± SD) 0.22 0.145 −0.01 0.921 41.92 ± 11.92 38.45 ± 10.14 0.171 Male sex (%) 43 (71.7) 16 (51.6) 0.095 BMI, kg/m2 (mean ± SD) 0.08 0.647 −0.02 0.922 22.44 ± 4.83 24.65 ± 9.52 0.327 Race-ethnicity (%) 0.299 Hispanic 3 (10.3) 4 (18.2) Non-Hispanic Black 21 (72.4) 17 (77.3) Non-Hispanic White 1 (3.4) 1 (4.5) 4 (13.8) 0 (0.0) Heart failure (%) 10 (16.7) 7 (22.6) 0.688 NNRTI (%) 30 (50.0) 18 (58.1) 0.611 PI (%) 20 (33.3) 9 (29.0) 0.857 Integrase (%) 34 (56.7) 17 (54.8) 1 Comorbid infections Active TB (%) 4 (8.2) 5 (20.0) 0.272 Pneumocystis pneumonia (%) 17 (35.4) 6 (27.3) 0.69 Left ventricular ejection fraction, % (mean ± SD) 52.52 (16.61) 53.79 (16.53) 0.796 Right ventricular systolic pressure, mm Hg (mean ± SD) 29.81 (10.15) 29.60 (11.24) 0.948 Mitral E/A ratio (mean ± SD) 1.16 (0.61) 1.39 (0.92) 0.352 LA systolic diameter, mm (mean ± SD) 34.00 (7.30) 35.16 (6.01) 0.575 LV end diastolic diameter, mm (mean ± SD) 49.04 (8.73) 47.93 (5.90) 0.676 Baseline markers CD4+ T cells/µL (median [IQR])b −0.03 0.848 −0.02 0.903 17.00 [8.00–41.00] 28.00 [8.00–47.50] 0.544 CD8+ T cells/µL (median [IQR])b 0.27 0.067 −0.13 0.387 373.00 [245.50–496.50] 393.00 [257.50–795.50] 0.306 CD4/CD8 ratio (median [IQR])b −0.52 0.0003 0.23 0.136 0.05 [0.03–0.10] 0.05 [0.03–0.08] 0.76 HIV viral load, copies/mL (median [IQR])b −0.07 0.656 0.04 0.810 156,623 [55,177–400,265] 242,793 [120,962–500,000] 0.105 d-dimer, ng/mL (median [IQR])b 0.13 0.394 0.03 0.865 1373.30 [856–2674] 2400 [1,434–3546] 0.027 CRP, ng/mL (median [IQR])b 0.30 0.042 0.04 0.774 5200 [1,223–17,432] 5869 [2,748–18,415] 0.388 IL-6, pg/mL (median [IQR])c −0.15 0.332 0.17 0.274 2.35 [1.59–5.00] 3.41 [2.13–5.93] 0.105 TNF-α, pg/mL (median [IQR])c −0.16 0.301 −0.10 0.539 9.08 [6.54–14.05] 13.26 [8.30–18.52] 0.026 Soluble CD14, ng/mL (median [IQR]) 0.11 0.481 0.02 0.903 2,610,237 [2,021,491–3,024,374] 2,505,229 [2,197,651–3,339,005] 0.519 Tissue factor, pg/mL (median [IQR]) 0.17 0.292 −0.23 0.155 80.55 [67.71–105.42] 94.15 [65.02–113.42] 0.874 Week 2 markers Change in CD4 from baseline to week 2 (median [IQR]) −0.18 0.240 0.15 0.329 24 [7–60] 57 [10–106] 0.087 CD4+ T cells/µL (median [IQR])b 0.03 0.824 −0.10 0.494 53.5 [23–100.5] 82 [30–153] 0.11 CD8+ T cells/µL (median [IQR])b 0.16 0.295 −0.01 0.935 417 [280–653] 492 [193–793] 0.983 CD4/CD8 ratio (median [IQR])b −0.15 0.326 0.09 0.564 0.10 [0.06–0.22] 0.16 [0.09–0.30] 0.148 HIV viral load, copies/mL (median [IQR])b −0.35 0.017 0.23 0.127 458 [233–1513] 699 [299–2910] 0.28 D-dimer, ng/mL (median [IQR])b 0.07 0.689 −0.03 0.864 969 [629–1836] 2354 [797–3920] 0.009 CRP, ng/mL (median [IQR])b 0.06 0.691 −0.06 0.695 6564 [1396–30,722] 32,795 [9,343–78,900] 0.001 IL-6, pg/mL (median [IQR])c −0.14 0.381 0.00 1.000 2.32 [1.22–5.13] 7.47 [2.63–16.52] <0.001 TNF-α, pg/mL (median [IQR])c −0.10 0.550 0.02 0.918 7.51 [4.76–13.08] 16.34 [8.42–25.66] 0.001 Soluble CD14, ng/mL (median [IQR]) 0.09 0.576 −0.04 0.813 2,257,003 [1,813,221–2,852,754] 2,742,045 [2,185,802–3,116,137] 0.086 Tissue factor, pg/mL (median [IQR]) 0.16 0.332 −0.30 0.067 84.16 [61.92–96.43] 86.23 [59.68–97.65] 0.96 Markers closest in time to echocardiogram (within 10 days) CD4+ T cells/µL (median [IQR])b −0.26 0.084 0.13 0.368 30.50 [11.00–57.50] 36 [14.00–73.50] 0.412 CD8+ T cells/µL (median [IQR])b 0.29 0.047 −0.10 0.491 371 [246.75–531.75] 455 [291.50–866.00] 0.197 CD4/CD8 ratio (median [IQR])b −0.52 0.0002 0.23 0.120 0.08 [0.03–0.15] 0.09 [0.03–0.20] 0.815 HIV viral load, copies/mL (median [IQR])b 0.25 0.096 −0.24 0.102 83,448 [1,825–194,913] 109,246.00 [623–300,598] 0.903 Bold P<0.05 significant for pairwise comparisons; Bonferroni-corrected P<0.0007 significant for multiple comparisons.aPearson correlation coefficients for continuous variable and Beta coefficients from linear regression for categorical variables, with P value calculated using the Wald test.bLog transformation performed because of nonnormal distribution of the variable.cSquare-root transformation performed because of nonnormal distribution of the variable.BMI, Body-mass index; LA, left atrial; LV, left ventricular; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TB, tuberculosis. In the overall study population included in primary analyses, a lower CD4/CD8 ratio at baseline and time of echo (post-ART) was associated with higher RVSP (Table 1). HIV viral load at baseline, week 2, and near the time of echo did not have a significant association with LVEF. The inflammatory markers at baseline or week 2 and the change in CD4 count from baseline to week 2 were not associated with LVEF or RVSP. There were no significant interactions between immune or inflammatory markers and sex with respect to echocardiographic parameters. In secondary analyses of associations of pre-ART laboratory and pre-ART echocardiographic measures (N = 73 with pre-ART echocardiography), higher CRP levels were associated with higher RVSP (r = 0.46, P = 0.00004) and a lower CD4/CD8 ratio was associated with higher RVSP (r = −0.39, P = 0.0009), although this did not meet significance after Bonferroni correction. DISCUSSION We investigated associations of immune and inflammatory markers with cardiac function among PWH who presented with advanced AIDS in the modern ART era and were followed prospectively after ART initiation. This provided the opportunity to understand the relationship between immune activation that occurs in patients with advanced AIDS before and after ART initiation, including those with IRIS and myocardial dysfunction that may contribute to a downstream risk of HF observed in PWH. We found that lower CD4/CD8 ratios pre-ART and after ART initiation were associated with higher RVSP on post-ART echocardiography.11 This finding is consistent with recent studies from the broader HIV population that demonstrate clear associations of lower CD4 counts with a higher HF risk.2,3 Whether HIV-related CD4 lymphopenia itself is a cause of cardiac dysfunction and HF or a proxy marker of other factors (virologic, inflammatory, or otherwise) that lead to HF merits investigation in future mechanistic and clinical studies. Furthermore, it is possible that relative depletion of CD4 compared with CD8 lymphocytes and a related shift toward amplified CD8-predominant immune activation may predispose to heightened inflammation (as observed in studies of immune-progressed HIV) and HF.1,12–18 Yet, interestingly, although pre-ART CRP levels were associated with higher pre-ART RVSP, the presence of IRIS or inflammatory markers at baseline and week 2 was not associated with post-ART LVEF or RVSP. This may reflect the limited sample size, early intervention with anti-inflammatory therapies, or other residual confounding and warrants further investigation. The limitations of our study include the sample size and possible selection bias because echocardiography was performed as clinically indicated. Nevertheless, this represents the largest study investigating cardiac function among PWH presenting with advanced AIDS in the modern ART era. Our finding that, among PWH presenting with very low CD4 counts, a lower CD4/CD8 ratio is associated with higher RVSP warrants further study and may have implications for HIV-associated HF.

4.0 When to start

To demonstrate the feasibility of integrated screening for cryptococcal antigenemia and tuberculosis (TB) before antiretroviral therapy (ART) initiation and to assess disease specific and all-cause mortality in the first 6 months of follow-up. We enrolled a cohort of HIV-infected, ART-naive adults with CD4 counts ≤250 cells per microliter in rural Uganda who were followed for 6 months after ART initiation. All subjects underwent screening for TB; those with CD4 ≤100 cells per microliter also had cryptococcal antigen (CrAg) screening. For those who screened positive, standard treatment for TB or preemptive treatment for cryptococcal infection was initiated, followed by ART 2 weeks later. Of 540 participants enrolled, pre-ART screening detected 10.6% (57/540) with prevalent TB and 6.8% (12/177 with CD4 count ≤100 cells/μL) with positive serum CrAg. After ART initiation, 13 (2.4%) patients were diagnosed with TB and 1 patient developed cryptococcal meningitis. Overall 7.2% of participants died (incidence rate 15.6 per 100 person-years at risk). Death rates were significantly higher among subjects with TB and cryptococcal antigenemia compared with subjects without these diagnoses. In multivariate analysis, significant risk factors for mortality were male sex, baseline anemia of hemoglobin ≤10 mg/dL, wasting defined as body mass index ≤15.5 kg/m, and opportunistic infections (TB, positive serum CrAg). Pre-ART screening for opportunistic infections detects many prevalent cases of TB and cryptococcal infection. However, severely immunosuppressed and symptomatic HIV patients continue to experience high mortality after ART initiation.

Letter to the Editor: Treatment as Prevention: Are HIV Clinic Patients Interested in Starting Antiretroviral Therapy to Decrease HIV Transmission?

IntroductionWe investigated the impact of increasing CD4 count eligibility for antiretroviral therapy (ART) initiation on advanced HIV disease (AHD) and tuberculosis (TB) prevalence and incidence among people living with HIV...

To the Editor: Infection with HIV is an important risk factor for tuberculosis (TB). One-half million cases of TB attributable to HIV infection occur worldwide each year.1 Since the advent of highly active antiretroviral therapy (HAART), the morbidity and mortality of HIV-infected patients have declined.2 However, concomitant TB treatment and HAART are hampered by a high pill burden, complex drug interactions, treatment-related adverse events, and paradoxic reactions.3,4 Studies that have assessed the effect of HAART in the course of TB and HIV coinfection are few.5-8 All these retrospective studies suggest that coinfected patients with a CD4 count <100 cells/mm3 would probably benefit from early initiation of HAART. Unlike other HIV-associated opportunistic infections, TB may occur at high CD4 cell counts. The indication for HAART in these particular cases has not been assessed, and current antiretroviral (ARV) treatment guidelines are based on expert opinion.9 We evaluated retrospectively 93 episodes of TB diagnosed in 87 HIV-infected patients from January 2000 to February 2004 at Bichat Hospital in an attempt to assess the clinical aspects and outcome of TB, according to the level of immunosuppression at TB diagnosis and to the prescription of HAART in the course of TB treatment. Of our 87 patients, 58 (67%) originated from sub-Saharan Africa. At baseline, the CD4 count was ≥250 cells/mm3 in 25 cases (27%; group 1) and <250 cells/mm3 in 68 cases (73%; group 2). The mean plasma viral load (log) was 4.68 ± 1.58. The clinical presentation, treatment, and outcome of TB cases are summarized in Table 1. TB treatment was completed in 61 (66%) of 93 cases. The standard 6-month course was applied in 9 of 61 cases. An extended duration of TB treatment was prescribed in 52 cases, mainly because of extrapulmonary disease. A total of 22 adverse events leading to a change in TB therapy were recorded in 20 cases (22%). Adverse events led to interruption of TB treatment in 12 cases (13%). Toxicity of TB treatment was observed in 14 cases (22%) with concomitant HAART and in 6 cases (21%) without concomitant HAART. The occurrence of TB treatment toxicity led to HAART interruption in 3 cases. In these 3 cases, HAART was initiated <1 month after TB treatment initiation.TABLE 1: Presentation, Treatment, and Outcome of TB CasesHAART was prescribed in 64 cases, including initiation of a first HAART regimen in 36 cases. In 29 cases, patients did not receive ARV therapy during treatment of TB. In group 1, HAART was not initiated in 11 naive patients and was interrupted in 5 patients previously exposed to HAART, although not immunosuppressed. In group 2, HAART was not initiated in 1 patient who died 1 month after TB diagnosis, in 6 patients who were lost to follow-up, and in 2 patients who interrupted TB treatment prematurely and experienced early TB relapse. In 4 cases, observance difficulties prevented initiation of ARV therapy. In the case of concomitant ARV and TB treatment, 12 (19%) of 64 patients described side effects motivating interruption or change of HAART. Eleven patients developed an immune reconstitution inflammatory syndrome (IRIS). In 9 cases, patients belonged to group 2. Ten patients were receiving ARV treatment. Overall, 19 patients (20%) were lost to follow-up. During TB therapy, 7 patients died. Six (86%) of 7 deaths occurred in group 2, with a CD4 count <100 cells/mm3 at the time of TB diagnosis. Six patients experienced TB relapse in 7 cases. In only 1 case did TB relapse occur despite well-conducted TB therapy of 12 months. During the study period, a further AIDS-defining event (ADE) occurred in 20 cases. The CD4 count was <100 cells/mm3 in 16 cases. In 60 cases, patients completed treatment and achieved TB cure. In group 1, the cure rate was 56%, whatever the prescription of HAART. None of the 16 patients who did not start HAART experienced a new ADE or a significant decrease in CD4 count (456 ± 141 cells/ mm3 vs. 493 ± 186 cells/mm3). In group 2, the cure rate was higher when patients received HAART (76% vs. 31% with and without HAART, respectively; P = 0.003). In this study, patients mainly originated from endemic countries for TB and HIV. This could explain the high proportion of patients who were not deeply immunosuppressed at the time of TB diagnosis. Overall, 19 patients (20%) were lost to follow-up. Because of this high proportion of patients lost to follow-up, only 66% of TB treatments were successfully completed. Leonard et al10 found that the major factor improving the prognosis of patients coinfected with TB and HIV from 1991 to 2000 was improved follow-up during TB treatment, leading to an increase in survival, especially between 1991 and 1994 before the advent of HAART. Nevertheless, there is evidence to support the benefit of HAART in reducing TB mortality in HIV-infected patients. Several retrospective studies showed an improvement in the survival of HIV-infected patients with TB in the era of HAART.11,12 The decision regarding when to initiate ARV therapy in patients with coinfection must balance the risk of HIV disease progression with the potential risk of drug toxicities. In our cohort, concomitant HAART significantly improved survival in patients with a CD4 count <250 cells/mm3. Patients with a CD4 count <100 cells/mm3 had a high risk of clinical events. These data are concordant with previously published studies, suggesting the high benefit of early HAART prescription in these subjects.5-8 The benefit of HAART in patients with a high CD4 cell count at TB diagnosis has not been clearly demonstrated. In our cohort, patients with a CD4 count ≥250 cells/mm3 experienced a similar cure rate, whatever the prescription of HAART. After 12 months, none of the 16 patients remaining free of HAART experienced a new ADE or a significant decrease in CD4 cell count. Although the initiation of HAART is not systematically recommended in asymptomatic patients with a CD4 count ≥250 cells/mm3, it is recommended in case of TB coinfection, whatever the level of immunosuppression.9,13 By contrast, our data suggest that TB should not always imply HAART initiation in this particular subgroup of subjects. In our cohort, the incidence of TB treatment side effects was not influenced by concomitant HAART. In case of early initiation of HAART, however, the occurrence of side effects often led to discontinuation of TB and ARV treatment. Previous cohort studies have shown various rates of TB treatment adverse events (12% to 54%).6,8,14,15 When only adverse events leading to discontinuation of TB treatment are considered, this incidence is the same in all studies (10% to 15%).8,14,15 An interruption or change in HAART occurred in 19% of our cases. Prospective studies evaluating HAART in HIV-infected patients with TB registered HAART adverse effects in 9% to 20% of the cases.16,17 Use of new ARV agents and better knowledge of drug interactions may explain the lower rate of side effects. In our cohort, an IRIS was diagnosed in 12% of cases. Almost all cases were observed in patients with a CD4 count <250 cells/mm3 at baseline and receiving concomitant TB and ARV treatment. The estimated incidence of IRIS in TB- and HIV-coinfected patients ranges from 8% to 36%.4,6,7 In conclusion, our study confirms that the prescription of HAART to HIV-infected patients with active TB at a low baseline CD4 cell count decreases the incidence of death and ADEs without increasing the incidence of adverse events related to TB treatment. Conversely, patients with a CD4 count >250 cells/mm3 may remain free of HAART, although TB is considered to be an ADE. Agnès Meybeck, MD* Claude Fortin, MD* Raymond Ruimy, PhD† Véronique Joly, MD* Patrick Yeni, MD* *Service de Maladies Tropicales et Infectieuses Hôpital Bichat-Claude Bernard Paris, France †Service de Bactériologie Hôpital Bichat-Claude Bernard Paris, France

CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.

Background:HIV treatment guidelines have evolved to recommend rapid antiretroviral therapy (ART) initiation. Data on the impact of these changes in the Americas region are scarce.Methods:This study included data from CCASAnet sites in Brazil, Haiti, Honduras, Mexico, and Peru. ART-naïve adults who started ART from 2006 to 2022 were included. Trends in CD4 count, tuberculosis (TB), and treatment initiation were described using cumulative probability and logistic and Cox regression models.Findings:Total 29,881 PLWH met inclusion criteria; 2179 (7.3%) were diagnosed with prevalent TB and 379 (1.2%) with incident TB within six months after ART initiation. For individuals without TB, enrolment CD4 count increased from 160 to 320 cells/mm3. Over the study period, TB prevalence declined from peak of 9.4% to 5.4%, and incident TB from 1.5% to 0.8%. Median time to ART initiation decreased from 476 to 1 day for PLWH without TB, and 98 to 16 days for those with prevalent TB; time to TB treatment also decreased.Conclusions:Time to ART initiation has decreased in the CCASAnet consortium, with the majority of PLWH now starting ART within a week after enrolment. There has also been a decline in the prevalence and incidence of concurrent TB disease.

Introduction The HIV/AIDS pandemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection in many developing countries. Treatment of Mycobacterium tuberculosis in persons with HIV infection presents several challenges to the clinician, particularly in resource-poor countries. As will be discussed in this paper, diagnosis of latent tuberculosis relies on tuberculin skin testing, which has poor sensitivity and reproducibility in immunocompromised patients. The World Health Organization (WHO) recommends treatment of active tuberculosis as the primary means of global tuberculosis control. In practice, treatment of active tuberculosis typically requires that a symptomatic patient self-report to a health service for evaluation and management. Even if this approach to tuberculosis control were sufficient, many logistic and clinical problems remain involving tuberculosis diagnosis and therapy in the patient with HIV/AIDS. Recognizing the significant clinical and public health challenges surrounding the treatment of tuberculosis in patients with HIV infection, this paper will address a number of issues relevant to the care of co-infected patients. These include current guidelines for the treatment of active tuberculosis, as well as the diagnosis and treatment of latent tuberculosis in HIV-positive patients. The paper concludes with a discussion of promising new drugs for tuberculosis treatment. Epidemiology of tuberculosis and HIV co-infection It is estimated that one-third of the world population is infected with M. tuberculosis, the large majority of whom live in the developing world. The HIV pandemic of the past two decades has led to a rise in the incidence of tuberculosis, particularly in sub-Saharan Africa. There is now an emerging pandemic of patients with HIV infection who are co-infected with tuberculosis. As of December 2000, the WHO estimated that approximately 36.1 million persons worldwide are living with HIV and nearly one-third of these persons are co-infected with M. tuberculosis[1]. Approximately 68% of persons co-infected with HIV and tuberculosis live in sub-Saharan Africa, while 22% live in Southeast Asia. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that approximately 40% of new tuberculosis cases among persons aged 15-44 years occur among individuals with HIV infection or AIDS. Tuberculosis rates among HIV-infected individuals in the United States, however, vary significantly among different groups, with highest rates among intravenous drug users and those who are foreign-born. Today, the burden of tuberculosis and HIV infections largely impacts the developing world, as well as the minority and low socio-economic individuals within industrialized countries. This paper will discuss issues in the treatment of M. tuberculosis in patients with HIV/AIDS; however, it is important to recognize that many patients co-infected with HIV and M. tuberculosis have limited or no access to essential diagnostic and therapeutic strategies. Escalating tuberculosis case rates over the past decade are largely attributable to HIV. Immunity to M. tuberculosis is partly under the control of the MHC class II restricted CD4 cells. With the progressive loss of CD4 cells, patients with HIV infection are at increased risk of reactivation of latent tuberculosis, as well as primary tuberculosis infection [2]. In turn, active tuberculosis infection appears to upregulate HIV replication, resulting in further immune compromise and accelerated HIV disease progression [3,4]. As a result, patients with HIV infection and active tuberculosis are at increased risk of opportunistic infections and associated mortality. The case fatality rate by the end of tuberculosis treatment is approximately 20% for new sputum smear-positive cases and up to 50% for new smear-negative cases [5]. Tuberculosis is the leading cause of death among persons with HIV/AIDS worldwide [6]. Guidelines for the treatment of active tuberculosis This section will review recent guidelines for the treatment of tuberculosis published by the Tuberculosis Committee of the Infectious Disease Society of America (IDSA) in conjunction with the American Thoracic Society (ATS) and the CDC [7,8]. In addition, we will review the Directly Observed Treatment Short-course (DOTS) strategy of the WHO for tuberculosis control worldwide. These published guidelines pertain to the treatment of tuberculosis without respect to the patient's HIV status. Modified recommendations for the treatment of tuberculosis in HIV-seropositive patients will be discussed in the following section. In April 2000, the IDSA published practice guidelines for the treatment of tuberculosis [7]. Table 1, adapted from the IDSA publication, lists the 10 essential recommendations for the treatment of patients with tuberculosis. Readers are referred to the original publication for detailed comments pertaining to these recommendations, as well as performance indicators. It should be noted that the IDSA recommendations were developed for use in industrialized nations such as the United States and are currently not feasible in many countries of the world. In Table 1, therefore, we have juxtaposed the WHO DOTS strategy guidelines for management of patients with tuberculosis.Table 1: Infectious Disease Society of America (IDSA) recommendations and World Health Organization Directly Observed Treatment Shortcourse (WHO DOTS) strategy for the management of patients with tuberculosis (TB).In geographic areas where ≥ 4% of the M. tuberculosis isolates are resistant to isoniazid, the IDSA, ATS, and CDC recommend that the usual three-drug regimen of isoniazid, rifampin and pyrazinamide be augmented with a fourth drug, either ethambutol or streptomycin. Clinicians will therefore need to be aware of the susceptibility patterns in their geographic area. In 1997, approximately 84% of the US population lived in states that had ≥ 4% of tuberculosis isolates resistant to isoniazid. Therefore, most patients in the United States should be started on an initial four-drug regimen. This is followed by isoniazid and rifampin for 18 weeks. Although a 6-month course of treatment is recommended, this should be extended to 9 months if there is a delay in AFB, culture conversion or clinical improvement for 8 weeks. The WHO Global Tuberculosis Programme (WHO/GTP) assists over 60 countries with national tuberculosis control and prevention. The priority of the WHO program has been active case finding and cure of infectious tuberculosis cases. In 1993, the WHO/GTP declared tuberculosis a global emergency and began promoting the DOTS strategy. The DOTS strategy consists of five key components: "1) Government commitment to sustained TB control activities; 2) Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services; 3) Standardized treatment regimen of six to eight months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial two months; 4) A regular, uninterrupted supply of all essential anti-tuberculosis drugs; and 5) A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control programme performance overall" [9] (see Table 1). According to the WHO/GTP, as of 1999, 127 countries had accepted the DOTS strategy and were implementing it to varying degrees [10]. Nevertheless, the WHO/GTP estimate that, in 1999, only 45% of the world population had access to DOTS and 23% of new smear-positive cases were referred to DOTS programs. In addition, there are often a complex array of political, financial, and infrastructure problems that impede local DOTS programs. The current WHO DOTS strategy does not incorporate the diagnosis and treatment of latent tuberculosis. Some experts believe that the DOTS strategy, which focuses exclusively on the treatment of active cases, is insufficient for the control and elimination of tuberculosis, particularly in the HIV/AIDS era [11]. It has been recommended that targeted diagnosis and treatment of latent tuberculosis infection among specific populations be added to national tuberculosis control programs. At present, WHO recommends treatment of latent tuberculosis in HIV-positive patients; but only in settings where it is possible to provide HIV testing and counseling, and where it is possible to exclude cases of active tuberculosis and ensure proper follow-up. The DOTS strategy also employs empiric anti-tuberculous therapy without mycobacterial cultures and drug susceptibility testing. Without drug susceptibility information, it is impossible to identify cases of drug-resistant tuberculosis and to avoid treatment failure and further transmission of drug-resistant strains. The WHO recognizes the threat of multidrug-resistant tuberculosis (MDR-TB) and, in July 1999, convened a working group on DOTS-Plus for the treatment of MDR-TB [12]. DOTS-Plus is a pilot program to provide second-line drugs (i.e., fluoroquinolones, amikacin, kanamycin, capreomycin, cycloserine, para-aminosalicylic acid, and ethionamide) to manage MDR-TB in resource-limited countries. This strategy does not, however, address the role of mycobacterial cultures and drug susceptibility testing for individualized drug therapy and the prevention of drug-resistant tuberculosis. Finally, because DOTS relies on patients self-reporting to health services, additional tuberculosis transmission can take place before the patient is evaluated and receives appropriate therapy. Modeling of the tuberculosis epidemic in Tanzania suggests that DOTS may slow the incidence rate, but in the face of the HIV epidemic is unlikely to reverse the upward trend [13]. Again, some experts advocate targeted case finding, particularly among high-risk groups [11,14]. Diagnosis and treatment of active tuberculosis infection in patients with HIV infection This section deals specifically with the treatment of active tuberculosis in HIV-infected individuals as recommended by the CDC [15,16]. Again, many people co-infected with HIV and tuberculosis in the developing world do not have access to the relevant diagnostic tests and anti-tuberculosis and antiretroviral therapies. To impact tuberculosis-associated morbidity and mortality worldwide, developing countries will require both the skills and commodities to diagnose and treat individuals effectively. At present, tuberculosis treatment for the HIV-positive patient as recommended by the CDC is not applicable in most resource-poor countries. Treatment of active and latent tuberculosis infection in patients with HIV depends on the application of both clinical judgment and appropriate diagnostic tests. Active tuberculosis can occur at any CD4 cell count but atypical presentations are more likely with advanced HIV disease or AIDS. Clinicians should be alert to the sometimes atypical presentations of pulmonary and extrapulmonary tuberculosis in HIV-infected patients. Sputum acid fast staining, mycobacterial cultures, and drug susceptibility testing are recommended in all patients suspected of having tuberculosis. However, patients with HIV are slightly less likely to have positive sputum smears than non-HIV-infected individuals [17]. Likewise, chest radiographic findings can vary depending on the degree of immunosuppression. Patients with CD4 cell counts greater than 200 are more likely to have classic findings of upper lobe infiltrates with cavitary lesions, while those patients with AIDS may more likely have hilar adenopathy and pleural effusions without cavitations [18]. Mycobacteremia and extrapulmonary tuberculosis, especially meningitis and adenopathy, also correlate with diminishing numbers of CD4 cells and degree of immunosuppression. Thus, for patients with HIV infection, the diagnosis of active tuberculosis is more challenging. Clinical suspicion of tuberculosis in a patient known or suspected of being HIV-infected should result in prompt initiation of anti-tuberculosis therapy regardless of sputum staining or radiograph findings. The 1998 CDC recommendations for the treatment of tuberculosis among patients infected with HIV are summarized in Table 2[15]. The treatment of tuberculosis in the HIV-seropositive patient may differ from the standard treatment in the following ways: (i) choice of anti-tubercular regimen and dose adjustments; (ii) duration of treatment (ideally with directly observed therapy); (iii) promotion of antiretroviral therapy; and (iv) monitoring requirements. Due to rapid advances in the management of HIV disease, it is recommended that all patients co-infected with HIV and tuberculosis should be evaluated by a specialist to ensure optimal management.Table 2: Tuberculosis (TB) treatment recommendations for the HIV-seropositive patient.The treatment algorithm begins with establishing the patient's HIV status and whether the patient is on optimal antiretroviral therapy. All patients diagnosed with active tuberculosis should be HIV tested and, if seropositive, evaluated for antiretroviral therapy. It was previously felt that the diagnosis of active tuberculosis should result in the deferral of antiretroviral therapy. Early initiation of antiretroviral therapy is now recommended. While being treated for tuberculosis, the HIV-positive patient not receiving concurrent HIV therapy should be reassessed every 3 months for initiation of antiretroviral therapy. Known or suspected HIV-positive patients should receive prompt initiation of effective anti-tuberculosis therapy. If antiretroviral therapy is not started, the patient can typically receive standard anti-tuberculosis therapy: isoniazid, rifampin, pyrazinamide, and ethambutol. If the patient is to receive simultaneous anti-tuberculosis and antiretroviral therapy, the selected regimens and doses must account for significant drug-drug interactions between the rifamycins (rifampin, rifabutin, rifapentine) and the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI). Rifamycins, particularly rifampin, induce the hepatic cytochrome P-450 (CYP450) and reduce the serum levels of protease inhibitors, NNRTI, and other drugs metabolized by the CYP450 system. The CDC generally recommends the substitution of rifabutin, a less potent CYP450 inducer, for rifampin to allow simultaneous use of protease inhibitors and NNRTI. The use of rifampin with protease inhibitors or NNRTI is contraindicated, except in three antiretroviral combinations: (i) the NNRTI efavirenz and two nucleoside reverse transcriptase inhibitors (NRTI); (ii) the protease inhibitor ritonavir and one or more NRTI; and (iii) the combination of ritonavir and saquinavir, either hard-gel or soft-gel capsules [16]. Table 3 lists the recommended anti-tubercular drug doses, depending on frequency of administration and concurrent antiretroviral use.Table 3: Anti-tubercular drug doses.If the HIV-positive patient is already on an effective anti-retroviral regimen at the time of tuberculosis diagnosis, it is desirable to continue the patient on the same antiretroviral regimen with appropriate dose adjustments. If the patient is starting a new antiretroviral regimen, options include: (i) a rifabutin-based regimen with the necessary protease inhibitor or NNRTI dose adjustments; (ii) a non-rifamycin-containing regimen such as isoniazid, streptomycin, pyrazinamide, ethambutol for 2 months, then isoniazid, streptomycin, ethambutol for 7 months; or (iii) a regimen that does not contain a protease inhibitor or NNRTI. Table 4 lists the recommended dose adjustments for rifabutin-based regimens. Given the complexity of these drug interactions, it is recommended that the selection of dual anti-tubercular and antiretroviral therapies be made following consultation with a specialist.Table 4: Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) dose adjustments with rifabutin.Among the protease inhibitors, ritonavir has the highest potency in inhibiting the CYP450 pathway. With any dose of ritonavir, including low-dose ritonavir 100 mg twice a day, a reduced dose of rifabutin (150 mg two or three times per week) is recommended. According to the 2000 CDC guidelines for the use of rifabutin or rifampin among patients taking protease inhibitors or NNRTI, co-administration of ritonavir with the usual dose of rifampin (600 mg daily or two or three times per week) may be an option but pharmokinetic and clinical data are limited [16]. As previously stated, a patient taking the combination of saquinavir (either the soft-gel or hard-gel capsule) and ritonavir should take the reduced dose of rifabutin (150 mg two or three times per week). The saquinavir-ritonavir combination may possibly be given with the usual dose of rifampin but, again, limited pharmacokinetic and clinical data are available. Saquinavir, as a sole protease inhibitor, is generally not recommended in combination with rifabutin because the serum levels of saquinavir may be decreased as much as 45%. Indinavir, nelfinavir, and amprenavir should not be used in combination with rifampin, but all three protease inhibitors can be administered with a reduced daily dose of rifabutin (150 mg daily) or the usual dose of rifabutin (300 mg two or three times per week). Efavirenz induces CYP450 and accelerates rifamycin metabolism; therefore, efavirenz should be co-administered with an increased dose of rifabutin (450 or 600 mg daily, or 600 mg two or three times per week). According to the recent CDC guidelines, efavirenz may be combined with the usual dose of rifampin (600 mg daily or two or three times per week). The NNRTI nevirapine should typically be given with the usual dose of rifabutin (300 mg daily or two or three times per week). If co-administration of nevirapine with rifampin is clearly indicated, careful monitoring is recommended. The use of delavirdine is contraindicated during the treatment of tuberculosis because the drug levels are markedly decreased with both rifampin and rifabutin. HIV-infected patients have a higher incidence of drug-resistant tuberculosis isolates than non-HIV-infected patients. There have been several reports of increased risk of rifampin resistance among HIV-positive patients [19-21]. Higher rates of drug-resistant tuberculosis in HIV-infected patients may be associated with biological, behavioral, and societal factors including drug malabsorption, non-adherence, nosocomial outbreaks, and inadequate drug therapy in countries with high rates of co-infection. Directly observed therapy, regarded as the best strategy for ensuring adherence and limiting drug-resistant tuberculosis, is recommended for all patients with HIV infection [15]. In a randomized, controlled trial of anti-tuberculosis therapy among HIV-positive patients in Baltimore, Maryland, patients who received supervised therapy for tuberculosis had better survival than those who self-administered therapy [22]. Treatment of drug-resistant tuberculosis involves initiation of a multi-drug regimen tailored to the susceptibility profile of the organism. Due to the diversity of resistance patterns, it is not possible to recommend standardized protocols for therapy. Any regimen should include two or more drugs to which the isolate is susceptible. For HIV-positive patients at risk of MDR-TB, defined as resistance to both isoniazid and rifampin, initial empiric treatment should include second-line tuberculosis drugs to which resistance is uncommon. The 1999 WHO Essential Drug List was to include the following second-line tuberculosis amikacin, kanamycin, capreomycin, cycloserine, acid, and and drug susceptibility testing should be on all tuberculosis isolates and the anti-tuberculosis regimens Although MDR-TB is associated with a high mortality rate especially in resource-poor countries where the detection of drug resistance to months, if at and the second-line drugs are often months is the duration of treatment for pulmonary tuberculosis among HIV-positive patients in the United States a regimen is used [15]. treatment is for patients with a clinical or conversion of sputum cultures from positive to Some experts recommend the use of treatment regimens in all patients with HIV infection, especially among patients with advanced [17]. duration of treatment is clearly recommended in patients with slow clinical or with or HIV-positive individuals with active tuberculosis to be at increased risk of tuberculosis of a 6-month regimen. A trial of isoniazid was among HIV-positive patients in who a 6-month regimen of isoniazid decreased the risk of a of tuberculosis among HIV-positive patients. This not whether these were to M. tuberculosis or both of which have previously been The recommend of isoniazid for HIV-positive patients of tuberculosis therapy. At present, the WHO and the CDC recommend a months of directly observed tuberculosis therapy without Treatment of latent tuberculosis infection in patients with HIV infection It is estimated that 2 people worldwide are infected with latent tuberculosis. Patients with HIV infection are at increased risk of to active disease [2]. In 2000, the and the CDC new guidelines for the diagnosis and treatment of latent tuberculosis infection This public health strategy both prevention by the latent infection before it to active infection and primary prevention by further tuberculosis In addition, the use of active antiretroviral therapy has been to reduce the incidence of tuberculosis among persons with HIV infection The new guidelines recommend targeted of populations and patients at increased risk of tuberculosis infection who from treatment to active for targeted include drug health care of and all patients with HIV Diagnosis of latent tuberculosis infection is on the tuberculin skin new including detection are being developed A has with tuberculin skin testing in are to the diagnostic of this in the United States and in populations with varying degrees of risk for latent tuberculosis. There be two significant of developing tests for the detection of latent M. tuberculosis tests the need for a health service at and their be less than tuberculin skin testing. of latent tuberculosis in an HIV-infected patient can be a diagnostic It has been that the sensitivity of tuberculin skin testing may be in patients with to as well as to and can in persons with HIV infection and of the is associated with higher CD4 cell For these testing is no recommended for the diagnosis of latent tuberculosis. guidelines are to treat latent tuberculosis infection in HIV-infected persons with at high-risk of latent tuberculosis or with recent to a case of active tuberculosis should receive therapy regardless of tuberculin has been the of treatment of latent tuberculosis clinical have a in the risk of to active tuberculosis following months of isoniazid therapy. The optimal duration of isoniazid therapy has also been including the trial of the Tuberculosis and in in the and this or months of isoniazid therapy months of isoniazid therapy reduced the tuberculosis incidence by with for months and 20% for 3 months; however, with months therapy was than for of therapy A recent of isoniazid therapy in that from isoniazid therapy 9 months, with no additional associated with therapy The new and CDC guidelines recommend isoniazid therapy for 9 months (300 mg isoniazid daily mg with months of therapy as a less The to isoniazid therapy include and poor Directly observed therapy has been to adherence but is not important in the treatment of latent tuberculosis has been the of regimens that may adherence and reduce have the of regimens for the treatment of latent tuberculosis in individuals A trial that daily rifampin and pyrazinamide for 2 months was to isoniazid for months for the treatment of latent tuberculosis in HIV-infected persons the of these the new guidelines regimens for the treatment of latent tuberculosis as summarized in Table from their publication rifampin and pyrazinamide for 2 months (600 mg rifampin daily pyrazinamide daily) is the regimen for HIV-infected patients and be for suspected cases of tuberculosis. should be for rifampin in patients receiving protease inhibitors or NNRTI, further is to in the treatment of latent tuberculosis. The same drug-drug interactions and dose adjustments for antiretroviral drugs and rifamycins It is that the also recommends the regimen for individuals the the clinical for this combination have been only in HIV-positive patients. If MDR-TB is the recommended therapy is pyrazinamide and ethambutol or pyrazinamide and a (i.e., or for Treatment for suspected to MDR-TB should be extended to months for HIV-positive American Thoracic Society and Centers for Disease Control and Prevention guidelines for the treatment of latent tuberculosis the use of rifampin pyrazinamide therapy in infected patients has been associated with a rate of patients with resulting from the use of therapy have been to the five of these patients on these CDC and have their 2000 recommendations The (i) that be used with particularly in patients with disease, on or those taking drugs; and (ii) that patients who are treated with be by a health care at and for a of tests and evaluation with a at 8 to treatment therapy with the regimen should be for significant rates of have not been observed in HIV-infected patients treated with this regimen, either in clinical or to the use of the regimen in For HIV-infected patients to persons with active tuberculosis, treatment for latent tuberculosis should be a tuberculin In addition, some experts advocate HIV-infected individuals who in high-risk evaluation for latent tuberculosis treatment should include a careful and and, chest radiograph to exclude active tuberculosis. anti-tubercular drugs in treatment of tuberculosis, particularly for MDR-TB, will on the of new anti-tubercular there are several drugs under that have in M. tuberculosis. In some cases the drug has also in a of tuberculosis, and some have received and Drug for other under include and other and is a rifamycin the serum of which is three times than that of the rifampin The of M. tuberculosis is to or one to that of Given the between and other rifamycin the of over rifampin pharmokinetic In the infected with tuberculosis and in tuberculosis a regimen is less active than a daily regimen, both rifamycins being given at 10 In tuberculosis however, the regimen is significantly less active than the daily regimen In the regimens during the of tuberculosis therapy may provide increased to as well as to health care programs. is an for and other infections that has in M. tuberculosis, to that of and in in a of tuberculosis that at 100 is as as isoniazid at and more than clinical are being to the role of in combination therapy active tuberculosis. and also promising in a of tuberculosis are a class of inhibitors with and The of at 100 is with isoniazid at per an by the and Drug for the treatment of appears to be less active M. tuberculosis than It has been recommended, however, for further at higher is a new to that has been to potent in M. in were also to be to this with of In a administration of this drug at a dose of per led to of disease burden in and with that with isoniazid per and issues in the treatment of tuberculosis in patients with HIV have previously to some of the and issues that the treatment of tuberculosis in resource-poor countries. At the and there may also some important and to effective tuberculosis treatment. A among tuberculosis patients in Tanzania that only of the patients had of the disease and treatment In a recent from people were generally well HIV but tuberculosis of and were to AIDS than tuberculosis. patients with tuberculosis were often as having AIDS. Due to the associated with the that patients with tuberculosis may not or to appropriate These the important impact that the HIV epidemic may have on the public and to tuberculosis. a epidemic of tuberculosis and HIV co-infection in many of the developing world. The increased of tuberculosis and HIV/AIDS and the rise of MDR-TB a health threat to all While significant have been made in developing regimens for the treatment of active and latent tuberculosis, therapy is and second-line drugs are drug resistance is for are the anti-tuberculosis of drugs such as and and the of which may treatment. The optimal use of these drugs in combination therapy is a promising of active In addition, we advocate the of new and tuberculosis drugs that will be made to patients in developing countries.

To determine and compare the clinical and immunologic outcomes for HIV-infected women initiated on antiretroviral therapy (ART), with and without previous exposure to single-dose nevirapine in the MTCT-Plus programme - Kampala, Uganda, from 2003 to 2011. Retrospective comparison of prospectively collected programmatic data of clinical and immunologic treatment outcomes among HIV-infected Ugandan women, with and without prior exposure to sdNVP, who received NNRTI-based ART for a median follow-up of 6years. Of the 408 women in the programme, 289 (70.8%) were started on ART, of whom 205 (70.9%) had prior exposure to sdNVP. Clinical, immunologic and combined (clinical and or immunologic) treatment failure occurred in 29 (10.0%), 132 (45.7%) and 142 (49.1%) women, respectively. There was no significant difference in the distribution of time to immunologic failure for women by exposure to sdNVP (log-rank P=0.98). In Cox proportional hazard modelling, exposure to sdNVP was not associated with immunologic failure [adjusted hazard ratio (HR)=0.89, 95% confidence interval (CI): 0.61-1.30]. CD4 count >100cells/mm(3) at initiation was associated with reduced incidence of immunologic failure in adjusted analyses (HR=0.32, 95% CI: 0.22-0.48). HIV-infected Ugandan women initiated on an NVP-based ART regimen had similar immunologic treatment outcomes irrespective of previous NVP exposure. CD4 cell count prior to initiating HAART was a key prognostic factor for successful long-term immunologic treatment outcomes. In poor settings, regular follow-up of patients on HAART with adequate counselling to promote adherence and safe disclosure may promote low clinical failure rates.

Given the lack of detailed studies on tuberculosis (TB) in patients on antiretroviral treatment (ART) in South-East Asia, we aimed to determine the incidence and risk factors for early (after ≤6 months of ART) and late (after >6 months of ART) incident TB in Cambodia. We conducted a retrospective analysis of all patients started on ART at a non-governmental hospital in Phnom Penh (March 2003-December 2010). TB diagnosis was performed according to WHO algorithms. Risk factor analysis was performed using multivariate Cox regression modeling. Overall, 2984 patients started ART. The median baseline CD4 count was 89 cells µl(-1) (IQR 25-209), median age 34 years (IQR 29-40). Fifty-three percent of the patients were female. Median follow-up time on ART was 2.4 years. In addition to 932 (31.2%) patients already on TB treatment at ART initiation, 313 (10.5%) developed TB, with an overall incidence rate of 3.9/100 patient-years. Of those developing TB, 179 (6.0%) patients were diagnosed with early TB and 134 (4.5%) with late TB, corresponding with a rate of 13.5 and 2.0 per 100 patient-years respectively. Risk factors for early TB included low body mass index, low baseline CD4 count and low hemoglobin levels. Low on-treatment CD4 counts and hemoglobin levels, being underweight while on ART and prevalent TB were identified as risk factors for late TB. The incidence of early TB was high, and predominantly associated with advanced HIV progression markers. Earlier ART initiation and enhanced TB screening prior to and after ART initiation is warranted. Late TB amounts to almost half of the total TB burden, meriting specific preventive and diagnostic approaches.

IntroductionThere is conflicting data on long-term CD4 immune recovery after combination antiretroviral therapy (ART) in resource-limited settings. Virologic suppression is rarely documented in cohorts from sub-Saharan Africa so objective evidence of adherence is biologically unsubstantiated. We sought to investigate long-term patterns of immune recovery in Ugandan patients on ART with sustained viral suppression.MethodsA prospective cohort of patients starting ART between April, 2004 and April, 2005 at the Infectious Diseases Institute with sustained viral suppression (viral load ≤400 copies/ml at month 6 and 12) while on first-line ART. Propensity scores were used to adjust for treatment allocation (nevirapine or efavirenz) at ART initiation. Data were analyzed using Kaplan Meier methods and cross-sectional time series regression.ResultsThree hundred and fifty-six patients were included in the analysis.71.6% were female, 87% in WHO stage 3 or 4, median age was 37 years, (IQR:32–43), and median CD4 count was 108 cells/µL, (IQR:35–174) at ART start. At multivariable analysis, lower immune recovery (measured by change in CD4 from ART start at each time interval) was associated with male-gender (-59, 95% CI: 90, -28, P<0.001), baseline CD4 count of 101–200 cells/µL (-35, 95% CI: 62, -9, P=0.009) and >200 (-64, 95% CI: 101, -26, P=0.001), and use of AZT at baseline (-47, 95% CI: -74, -20, P=0.001). Median time to reach >400 cells/µL was longer in males (197.4 weeks, IQR:119.9–312.0), compared to females (144.7 weeks, IQR:96.6–219.7, P<0.001). The cumulative probability of attaining CD4 >400 cells/µL over 7 years was higher in females compared to males (P<0.001).ConclusionsThere was long-term, continuous, immunologic recovery up to 7 years after ART initiation in an urban Ugandan cohort. Virologically suppressed women had better sustained immune recovery than men. Men take longer to immune reconstitute and have a lower probability of reaching a CD4 cell count >400 cells/µL. The biologic mechanisms of these gender differences need further exploration.

How can this be? Preventing death in patients with HIV-associated tuberculosis [Editorial