Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe

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.

The Individualized Genetic Barrier Predicts Treatment Response in a Large Cohort of HIV-1 Infected Patients

The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus' genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests.

Hyaluronic Acid Levels Predict Risk of Hepatic Encephalopathy and Liver-Related Death in HIV/Viral Hepatitis Coinfected Patients

Background Whereas it is well established that various soluble biomarkers can predict level of liver fibrosis, their ability to predict liver-related clinical outcomes is less clearly established, in particular among HIV/viral hepatitis co-infected persons. We investigated plasma hyaluronic acid’s (HA) ability to predict risk of liver-related events (LRE; hepatic coma or liver-related death) in the EuroSIDA study. Methods Patients included were positive for anti-HCV and/or HBsAg with at least one available plasma sample. The earliest collected plasma sample was tested for HA (normal range 0–75 ng/mL) and levels were associated with risk of LRE. Change in HA per year of follow-up was estimated after measuring HA levels in latest sample before the LRE for those experiencing this outcome (cases) and in a random selection of one sixth of the remaining patients (controls). Results During a median of 8.2 years of follow-up, 84/1252 (6.7%) patients developed a LRE. Baseline median (IQR) HA in those without and with a LRE was 31.8 (17.2–62.6) and 221.6 ng/mL (74.9–611.3), respectively (p<0.0001). After adjustment, HA levels predicted risk of contracting a LRE; incidence rate ratios for HA levels 75–250 or ≥250 vs. <75 ng/mL were 5.22 (95% CI 2.86–9.26, p<0.0007) and 28.22 (95% CI 14.95–46.00, p<0.0001), respectively. Median HA levels increased substantially prior to developing a LRE (107.6 ng/mL, IQR 0.8 to 251.1), but remained stable for controls (1.0 ng/mL, IQR –5.1 to 8.2), (p<0.0001 comparing cases and controls), and greater increases predicted risk of a LRE in adjusted models (p<0.001). Conclusions An elevated level of plasma HA, particularly if the level further increases over time, substantially increases the risk of contracting LRE over the next five years. HA is an inexpensive, standardized and non-invasive supplement to other methods aimed at identifying HIV/viral hepatitis co-infected patients at risk of hepatic complications.

A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients

Because of the large variability in the pharmacokinetics of anti-HIV drugs, therapeutic drug monitoring in patients may contribute to optimize the overall efficacy and safety of antiretroviral therapy. An LC–MS/MS method for the simultaneous assay in plasma of the novel antiretroviral agents rilpivirine (RPV) and elvitegravir (EVG) has been developed to that endeavor. Plasma samples (100 μL) extraction is performed by protein precipitation with acetonitrile, and the supernatant is subsequently diluted 1:1 with 20-mM ammonium acetate/MeOH 50:50. After reverse-phase chromatography, quantification of RPV and EVG, using matrix-matched calibration samples, is performed by electrospray ionization–triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The stable isotopic-labeled compounds RPV-13C6 and EVG-D6 were used as internal standards. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<6.4%), as well as EVG and RPV short and long-term stability in plasma. Calibration curves were validated over the clinically relevant concentrations ranging from 5 to 2500 ng/ml for RPV and from 50 to 5000 ng/ml for EVG. The method is precise (inter-day CV%: 3–6.3%) and accurate (3.8–7.2%). Plasma samples were found to be stable (<15%) in all considered conditions (RT/48 h, +4°C/48 h, −20°C/3 months and 60°C/1 h). Selected metabolite profiles analysis in patients' samples revealed the presence of EVG glucuronide, that was well separated from parent EVG, allowing to exclude potential interferences through the in-source dissociation of glucuronide to parent drug. This new, rapid and robust LCMS/MS assay for the simultaneous quantification of plasma concentrations of these two major new anti-HIV drugs EVG and RPV offers an efficient analytical tool for clinical pharmacokinetics studies and routine therapeutic drug monitoring service.

Impact of Switching From Zidovudine to Tenofovir Disoproxil Fumarate on Bone Mineral Density and Markers of Bone Metabolism in Virologically Suppressed HIV-1 Infected Patients; A Substudy of the PREPARE Study

Context: In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown. Methods: We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified. Results: Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, −1.73 (2.76)% vs AZT/3TC, −0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, −1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = −0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001). Conclusion: A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo.

Risk of Cardiovascular Events and Blood Pressure Control in Hypertensive HIV-Infected Patients: HIV Cohort Study (SHCS)

Background: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals. Methods: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement. Results: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of −0.82 (−1.06 to −0.58) mm Hg and −0.89 (−1.05 to −0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor–based and triple nucleoside regimens were associated with cardiovascular events. Conclusions: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.

Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy

Objective: To determine changes of cerebrospinal fluid (CSF) biomarkers of patients on monotherapy with lopinavir/ritonavir. Design: The Monotherapy Switzerland/Thailand study (MOST) trial compared monotherapy with ritonavir-boosted lopinavir with continued therapy. The trial was prematurely stopped due to virological failure in six patients on monotherapy. It, thus, offers a unique opportunity to assess brain markers in the early stage of HIV virological escape. Methods: Sixty-five CSF samples (34 on continued therapy and 31 on monotherapy) from 49 HIV-positive patients enrolled in MOST. Using enzyme-linked immunosorbent assay, we determined the CSF concentration of S100B (astrocytosis), neopterin (inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-β 1–42 (Aβ), the latter three indicating neuronal damage. Controls were CSF samples of 29 HIV-negative patients with Alzheimer dementia. Results: In the CSF of monotherapy, concentrations of S100B and neopterin were significantly higher than in continued therapy (P = 0.006 and P = 0.013, respectively) and Alzheimer dementia patients (P < 0.0001 and P = 0.0005, respectively). In Alzheimer dementia, concentration of Aβ was lower than in monotherapy (P = 0.005) and continued therapy (P = 0.016) and concentrations of tTau were higher than in monotherapy (P = 0.019) and continued therapy (P = 0.001). There was no difference in pTau among the three groups. After removal of the 16 CSF with detectable viral load in the blood and/or CSF, only S100B remained significantly higher in monotherapy than in the two other groups. Conclusion: Despite full viral load-suppression in blood and CSF, antiretroviral monotherapy with lopinavir/ritonavir can raise CSF levels of S100B, suggesting astrocytic damage.

The rate of recovery in renal function when patients with HIV infection discontinue treatment with tenofovir

OBJECTIVES Tenofovir is associated with reduced renal function. It is not clear whether patients can be expected to fully recover their renal function if tenofovir is discontinued. METHODS We calculated the estimated glomerular filtration rate (eGFR) for patients in the Swiss HIV Cohort Study remaining on tenofovir for at least 1 year after starting a first antiretroviral therapy regimen with tenofovir and either efavirenz or the ritonavir-boosted protease inhibitor lopinavir, atazanavir or darunavir. We estimated the difference in eGFR slope between those who discontinued tenofovir after 1 year and those who remained on tenofovir. RESULTS A total of 1049 patients on tenofovir for at least 1 year were then followed for a median of 26 months, during which time 259 patients (25%) discontinued tenofovir. After 1 year on tenofovir, the difference in eGFR between those starting with efavirenz and those starting with lopinavir, atazanavir and darunavir was - 0.7 [95% confidence interval (CI) -2.3 to 0.8], -1.4 (95% CI -3.2 to 0.3) and 0.0 (95% CI -1.7 to 1.7) mL/min/1.73 m(2) , respectively. The estimated linear rate of decline in eGFR on tenofovir was -1.1 (95% CI -1.5 to -0.8) mL/min/1.73 m(2) per year and its recovery after discontinuing tenofovir was 2.1 (95% CI 1.3 to 2.9) mL/min/1.73 m(2) per year. Patients starting tenofovir with either lopinavir or atazanavir appeared to have the same rates of decline and recovery as those starting tenofovir with efavirenz. CONCLUSIONS If patients discontinue tenofovir, clinicians can expect renal function to recover more rapidly than it declined.

Predicting smoking cessation and its relapse in HIV-infected patients: the Swiss HIV Cohort Study

OBJECTIVES: The aim of the study was to assess whether prospective follow-up data within the Swiss HIV Cohort Study can be used to predict patients who stop smoking; or among smokers who stop, those who start smoking again. METHODS: We built prediction models first using clinical reasoning ('clinical models') and then by selecting from numerous candidate predictors using advanced statistical methods ('statistical models'). Our clinical models were based on literature that suggests that motivation drives smoking cessation, while dependence drives relapse in those attempting to stop. Our statistical models were based on automatic variable selection using additive logistic regression with component-wise gradient boosting. RESULTS: Of 4833 smokers, 26% stopped smoking, at least temporarily; because among those who stopped, 48% started smoking again. The predictive performance of our clinical and statistical models was modest. A basic clinical model for cessation, with patients classified into three motivational groups, was nearly as discriminatory as a constrained statistical model with just the most important predictors (the ratio of nonsmoking visits to total visits, alcohol or drug dependence, psychiatric comorbidities, recent hospitalization and age). A basic clinical model for relapse, based on the maximum number of cigarettes per day prior to stopping, was not as discriminatory as a constrained statistical model with just the ratio of nonsmoking visits to total visits. CONCLUSIONS: Predicting smoking cessation and relapse is difficult, so that simple models are nearly as discriminatory as complex ones. Patients with a history of attempting to stop and those known to have stopped recently are the best candidates for an intervention.

PCR identification of HIV-1 DNA sequences in brain tissue of patients with AIDS encephalopathy.

We analyzed brain tissue from 39 patients for the presence of proviral HIV-1 sequences, using the polymerase chain reaction (PCR) for the amplification of segments of the viral LTR and gag genes. A novel primer extension procedure allowed the detection of a single HIV-1 copy in 1 micrograms DNA. We detected proviral HIV-1 DNA in 16 of 25 brain samples from AIDS patients. Semiquantitative evaluation of the amplified DNAs indicated considerable variation in viral load. Highest levels of proviral DNA were present in brain samples from six patients with clinical evidence of HIV-associated cognitive/motor complex and the histopathologic correlate of HIV leukoencephalopathy or HIV encephalitis. An additional 11 brain samples contained smaller amounts of proviral DNA. In these patients, clinical data were inconclusive regarding the diagnosis of HIV-1 encephalopathy and histopathologically there was no evidence of HIV-1-induced tissue lesions. In nine of 25 seropositive patients with AIDS (36%), brain samples scored negative or did not contain an unequivocal signal indicating the presence of proviral DNA. HIV-1 sequences were not detected in any of 14 control brain samples from HIV-1 seronegative patients. Our data indicate that HIV-1 is present in the central nervous system of the majority (two thirds) of AIDS patients and that the highest levels of proviral DNA in brain tissue are associated with HIV encephalopathy.

Efficacy of lead-in silibinin and subsequent triple therapy in difficult-to-treat HIV/hepatitis C virus-coinfected patients

OBJECTIVES: The efficacy of current hepatitis C virus (HCV) triple therapy, including a protease inhibitor, is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and nonresponse to previous peginterferon-ribavirin. These patients have a low chance (only 30%) of achieving a sustained virological response (SVR) during triple therapy and cannot wait for next-generation anti-HCV drugs. In a pilot study, we investigated the efficacy of a lead-in therapy with silibinin before triple therapy in difficult-to-treat patients. METHODS: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented failure of previous peginterferon-ribavirin treatment. Intervention was lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days. Subsequently, peginterferon-ribavirin combined with telaprevir was initiated for 12 weeks, followed by peginterferon-ribavirin dual therapy until week 48 after initiation of triple therapy. The outcome measurements were HCV RNA after silibinin lead-in, at weeks 2, 4 and 12 of triple therapy, and SVR at week 24 after the end of treatment. RESULTS: We examined six HIV/HCV-coinfected patients (four infected with genotype 1a). All had fibrosis grade METAVIR ≥F3 and were on fully suppressive antiretroviral therapy. Mean HCV RNA decline after silibinin therapy was 2.6 log10 IU/mL (range 2-3 log10 IU/mL). Five of the six patients were virologically suppressed at weeks 2 and 4, and all six at week 12 of triple therapy. One experienced a viral breakthrough thereafter. Four of five patients (80%) showed an SVR 24. One patient had an SVR 12 but has not yet reached week 24. CONCLUSIONS: A lead-in with silibinin before triple therapy is highly effective and increases the probability of HCV treatment success in difficult-to-treat HIV/HCV-coinfected patients with advanced liver fibrosis and previous failure of peginterferon-ribavirin.

Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study

BACKGROUND Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). METHODS In this retrospective study (2000-2011), pLLV was defined as a VL of 21-400 copies/mL on ≥3 consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥3 consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/mL. RESULTS Among 9972 patients, 179 had pLLV and 5389 were controls. Compared to controls, pLLV patients were more often on unboosted PI-based (adjusted odds ratio, aOR, [95%CI] 3.2 [1.8-5.9]) and NRTI-only combinations (aOR 2.1 [1.1-4.2]) than on NNRTI and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF, and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8-315]), unboosted PI-based (aOR 12.8 [1.7-96]) or NRTI-only combinations (aOR 115 [6.8-1952]), and VLs>200 during pLLV (aOR 3.7 [1.1-12]). No VF occurred in patients with persistent very LLV (pVLLV, 21-49 copies/mL; N=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared to 19/74 (26%) without change (P<0.001). CONCLUSIONS Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL ≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV >200 copies/ml.

Kaposi's Sarcoma in HIV-infected patients in South Africa: Multicohort study in the antiretroviral therapy era

The incidence of Kaposi's Sarcoma (KS) is high in South Africa but the impact of antiretroviral therapy (ART) is not well defined. We examined incidence and survival of KS in HIV-infected patients enrolled in South African ART programs. We analyzed data of three ART programs: Khayelitsha township and Tygerberg Hospital programs in Cape Town and Themba Lethu program in Johannesburg. We included patients aged >16 years. ART was defined as a regimen of at least three drugs. We estimated incidence rates of KS for patients on ART and not on ART. We calculated Cox models adjusted for age, sex and time-updated CD4 cell counts and HIV-1 RNA. A total of 18,254 patients (median age 34.5 years, 64% female, median CD4 cell count at enrolment 105 cells/μL) were included. During 37,488 person-years follow-up 162 patients developed KS. The incidence was 1,682/100,000 person-years (95% confidence interval [CI] 1,406-2,011) among patients not receiving ART and 138/100,000 person-years (95% CI 102-187) among patients on ART. The adjusted hazard ratio comparing time on ART with time not on ART was 0.19 (95% CI 0.13-0.28). Low CD4 cell counts (time-updated) and male sex were also associated with KS. Estimated survival of KS patients at one year was 72.2% (95% CI 64.9-80.2) and higher in men than in women. The incidence of KS is substantially lower on ART than not on ART. Timely initiation of ART is essential to prevent KS and KS-associated morbidity and mortality in South Africa and other regions in Africa with a high burden of HIV.

The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients.

BACKGROUND Cytomegalovirus (CMV) retinitis is a major cause of visual impairment and blindness among patients with uncontrolled HIV infections. Whereas polymorphisms in interferon-lambda 3 (IFNL3, previously named IL28B) strongly influence the clinical course of hepatitis C, few studies examined the role of such polymorphisms in infections due to viruses other than hepatitis C virus. OBJECTIVES To analyze the association of newly identified IFNL3/4 variant rs368234815 with susceptibility to CMV-associated retinitis in a cohort of HIV-infected patients. DESIGN AND METHODS This retrospective longitudinal study included 4884 white patients from the Swiss HIV Cohort Study, among whom 1134 were at risk to develop CMV retinitis (CD4 nadir <100 /μl and positive CMV serology). The association of CMV-associated retinitis with rs368234815 was assessed by cumulative incidence curves and multivariate Cox regression models, using the estimated date of HIV infection as a starting point, with censoring at death and/or lost follow-up. RESULTS A total of 40 individuals among 1134 patients at risk developed CMV retinitis. The minor allele of rs368234815 was associated with a higher risk of CMV retinitis (log-rank test P = 0.007, recessive mode of inheritance). The association was still significant in a multivariate Cox regression model (hazard ratio 2.31, 95% confidence interval 1.09-4.92, P = 0.03), after adjustment for CD4 nadir and slope, HAART and HIV-risk groups. CONCLUSION We reported for the first time an association between an IFNL3/4 polymorphism and susceptibility to AIDS-related CMV retinitis. IFNL3/4 may influence immunity against viruses other than HCV.

Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries.

SETTING Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.