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1.  Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy 
The New England journal of medicine  2010;362(8):697-706.
Despite high mortality rates in tuberculosis patients with HIV co-infection, there is continued controversy on when to initiate antiretroviral therapy (ART) in these patients.
Methods
We conducted an open-label randomized controlled trial in Durban, South Africa to determine optimal timing of ART initiation in relation to TB treatment. Acid-fast bacilli (AFB) smear positive tuberculosis patients with HIV infection and CD4+ counts <500 cells/mm3 (n=642) were randomized to one of two integrated treatment arms (ART initiation during tuberculosis treatment) or to a sequential treatment arm (ART initiation upon tuberculosis treatment completion). Participants received standard tuberculosis therapy, cotrimoxazole prophylaxis and once daily didanosine, lamivudine and efavirenz ART regimen. The primary endpoint was all-cause mortality.
Results
This analysis compares data from the sequential treatment arm and the combined integrated treatment arms up to 1 September 2008, when the Safety Monitoring Committee recommended halting the sequential treatment arm. Demographic, clinical and laboratory characteristics at baseline and adverse event rates during follow-up were similar in the study arms. Mortality was 56% lower (hazard ratio: 0.44; 95% Confidence Interval: 21% to 75%; p = 0.003) in the integrated arm (5.4 per 100 person-years (25 deaths; n=429)) compared to sequential arm (12.1 per 100 person-years (27 deaths; n=213)). Mortality rates were lower regardless of CD4+ count level.
Conclusions
Initiating ART during tuberculosis treatment in AFB positive patients with HIV co-infection and CD4+ counts <500 cells/mm3 significantly improves survival and provides further impetus for the integration of tuberculosis and AIDS services.
doi:10.1056/NEJMoa0905848
PMCID: PMC3076221  PMID: 20181971
2.  Immune Reconstitution Inflammatory Syndrome following Antiretroviral Therapy Initiation in Tuberculosis Patients: Findings from the SAPiT Trial 
Annals of internal medicine  2012;157(5):313-324.
Background
Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients.
Objective
We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB).
Setting
An outpatient clinic in Durban, South Africa
Patients
642 HIV-TB co-infected patients
Design
In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored.
Results
IRIS incidence was 19.5 (n=43), 7.5 (n=18) and 8.1 (n=19) per 100 person-years in the early integrated-, late integrated-, and sequential-treatment arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms.
Limitation
IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis.
Conclusion
Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996
doi:10.7326/0003-4819-157-5-201209040-00004
PMCID: PMC3534856  PMID: 22944873
3.  Initial Response to Protease-Inhibitor-Based Antiretroviral Therapy among Children less than Two Years of Age in South Africa: Effect of Co-treatment for Tuberculosis 
The Journal of infectious diseases  2010;201(8):1121-1131.
Background
South African guidelines recommend protease-inhibitor (PI)-based antiretroviral therapy (ART) with lopinavir/ritonavir (LPV/r) for HIV-infected children <36 months of age. We investigated factors associated with viral suppression and mortality among young children initiating ART.
Methods
Treatment-naive, ART-eligible, HIV-infected children, ages 6-104 weeks, were enrolled in an ART strategies trial in South Africa and initiated PI-based ART. Mortality and the probability of viral suppression (HIV RNA <400 copies/ml) by 39 weeks after ART initiation, were investigated.
Results
254 children initiated ART of whom 39% were co-treated for TB during follow up. The mortality rate was 14%. Factors predicting mortality were lower pre-ART weight-for-age z-sores and higher HIV RNA. 84% of surviving children suppressed by 39 weeks. Children not co-treated for TB were more likely to suppress (94.8%) than children co-treated at ART initiation (74.2%) or who started TB co-treatment after ART initiation (51.6%), (p<0.0001). Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z-scores, higher HIV RNA and WHO stage.
Conclusions
High rates of viral suppression can be achieved among infants and young children initiating PI-based ART. Co-treatment for TB reduced viral suppression. How best to treat HIV-infected children who require TB treatment warrants urgent investigation.
doi:10.1086/651454
PMCID: PMC2946637  PMID: 20214476
virologic suppression; pediatric HIV Infection; TB treatment; antiretroviral therapy; age
4.  Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township 
BMC Infectious Diseases  2011;11:258.
Background
Delays in the initiation of antiretroviral therapy (ART) in patients with HIV-associated tuberculosis (TB) are associated with increased mortality risk. We examined the timing of ART among patients receiving care provided by non-integrated TB and ART services in Cape Town, South Africa.
Methods
In an observational cohort study, we determined the overall time delay between starting treatment for TB and starting ART in patients treated in Gugulethu township between 2002 and 2008. For patients referred from TB clinics to the separate ART clinic, we quantified and identified risk factors associated with the two component delays between starting TB treatment, enrolment in the ART clinic and subsequent initiation of ART.
Results
Among 893 TB patients studied (median CD4 count, 81 cells/μL), the delay between starting TB treatment and starting ART was prolonged (median, 95 days; IQR = 49-155). Delays were shorter in more recent calendar periods and among those with lower CD4 cell counts. However, the median delay was almost three-fold longer for patients referred from separate TB clinics compared to patients whose TB was diagnosed in the ART clinic (116 days versus 41 days, respectively; P < 0.001). In the most recent calendar period, the proportions of patients with CD4 cell counts < 50 cells/μL who started ART within 4 weeks of TB diagnosis were 11.1% for patients referred from TB clinics compared to 54.6% of patients with TB diagnosed in the ART service (P < 0.001).
Conclusions
Delays in starting ART were prolonged, especially for patients referred from separate TB clinics. Non-integration of TB and ART services is likely to be a substantial obstacle to timely initiation of ART.
doi:10.1186/1471-2334-11-258
PMCID: PMC3203070  PMID: 21957868
5.  Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis 
The New England Journal of Medicine  2011;365(16):1482-1491.
Background
Antiretroviral therapy (ART) is indicated during tuberculosis (TB) treatment of patients infected with HIV-1, but the urgency to start ART at TB diagnosis for patients of varying levels of immune compromise is not known.
Methods
We conducted an open label, randomized study comparing immediate (within 2 weeks of TB treatment initiation) to early (8–12 weeks) ART among HIV-1 infected patients with CD4+ lymphocytes < 250/mm3 and suspected TB. The primary study endpoint was proportion of patients who survived without an AIDS-defining illness at 48 weeks.
Results
809 patients with median baseline CD4+ lymphocytes of 77 cells/mm3 and HIV-1 RNA of 5.43 log10 copies/mL were enrolled. In the immediate arm, 12.9% of patients experienced an AIDS-defining illness or death by 48 weeks compared to 16.1% in the early arm (p=0.45; 95% confidence interval (CI) for difference: −1.8%, 8.1%). In patients with screening CD4+ lymphocytes <50 cells/mm3, 15.5% of patients on the immediate arm vs. 26.6% on early ART experienced an AIDS defining illness or death (p=0.02; difference CI: 1.5%, 20.5%). TB immune reconstitution inflammatory syndrome (IRIS) was more common with immediate ART (11% vs. 5%: p=0.002). Viral suppression at 48 weeks was 74% and did not differ between arms (p=0.38).
Conclusion
Overall, immediate ART did not reduce AIDS-defining illnesses and death compared to early ART. For persons with CD4+ lymphocytes < 50 cells/mm3, immediate ART had 42% less AIDS defining illnesses and death compared to early ART. (ClinicalTrial.gov number NCT00108862.)
doi:10.1056/NEJMoa1013607
PMCID: PMC3327101  PMID: 22010914
6.  When to start antiretroviral therapy during tuberculosis treatment 
Purpose of review
Effective treatment exists for TB and for HIV but treating both diseases simultaneously presents several challenges. This review assessed the evidence for timing of antiretroviral therapy (ART) initiation in patents co-infected with TB.
Recent findings
Published evidence clearly demonstrates that TB HIV integration is essential for improved survival, but the question of when to start ART during TB treatment is more complex. Five randomised controlled trials assessed this question; four trials showed no difference in incidence rates of AIDS or death between TB patients initiating ART within 2 months compared to later during TB therapy, while one trial showed a significant survival gain with ART initiation within 2 weeks of TB therapy start. All five studies found improved AIDS-free survival with earlier ART initiation in TB patients with low CD4+ T-cell counts, except among patients with TB meningitis. The survival benefit was however, accompanied by increased immune reconstitution inflammatory syndrome events.
Summary
The trial data support the World Health Organisation recommendations on when to start ART in TB-HIV co-infected patients including earlier ART initiation in severely immune-compromised patients. However, several challenges remain in integrating TB and HIV treatment in public health care services. Additional research on timing of ART is needed for patients with drug-resistant and extra-pulmonary TB, notably TB meningitis.
doi:10.1097/QCO.0b013e32835ba8f9
PMCID: PMC3616247  PMID: 23188213
HIV; tuberculosis; antiretroviral therapy; immune reconstitution inflammatory syndrome (IRIS)
7.  Temporal Association Between Incident Tuberculosis and Poor Virological Outcomes in a South African Antiretroviral Treatment Service 
Introduction:
The temporal relationship between incident tuberculosis (TB) and virological outcomes during antiretroviral therapy (ART) is poorly defined. This was studied in a cohort in Cape Town, South Africa.
Methods:
Data regarding TB diagnoses, ART regimens, and 4-monthly updated viral load (VL) and CD4 count measurements were extracted from a prospectively maintained database. Rates of virological breakthrough (VL > 1000 copies/mL) and failure (VL > 1000 copies/mL on serial measurements) following initial VL suppression were calculated. Poisson models were used to calculate incidence rate ratios (IRRs) and identify risk factors for these virological outcomes.
Results:
Incident TB was diagnosed in 391 (28.5%) of 1370 patients during a median of 5.2 years follow-up. Five hundred seventy-eight episodes of virological breakthrough and 231 episodes of virological failure occurred, giving rates of 10.0 episodes per 100 person-years and 4.0 episodes per 100 person-years, respectively. In multivariate analyses adjusted for baseline and time-updated risk factors, TB was an independent risk factor for adverse virological outcomes. These associations were strongly time dependent; the 6-month period following diagnosis of incident TB was associated with a substantially increased risk of virological breakthrough (IRR: 2.3, 95% confidence interval: 1.7 to 3.2) and failure (IRR: 2.6, 95% confidence interval: 1.6 to 4.3) compared with time without a TB diagnosis. Person-time preceding TB diagnosis or more than 6 months after a TB diagnosis was not associated with poor virological outcomes.
Conclusions:
Incident TB during ART was strongly associated with poor virological outcomes during the 6-month period following TB diagnosis. Although underlying mechanisms remain to be defined, patients with incident TB may benefit from virological monitoring and treatment adherence support.
doi:10.1097/QAI.0b013e3182a23e9a
PMCID: PMC3819359  PMID: 23846570
tuberculosis; HIV; viral load; virological failure; antiretroviral; Africa
8.  Effects of Tuberculosis on the Kinetics of CD4+ T Cell Count Among HIV-Infected Patients Who Initiated Antiretroviral Therapy Early After Tuberculosis Treatment 
Abstract
The effects of tuberculosis (TB) on the kinetics of CD4+ T cells among HIV-infected individuals with early combination antiretroviral therapy (cART) after TB therapy initiation are poorly characterized. We conducted a case-control study with 15 HIV-TB-coinfected patients who initiated TB treatment and early cART, and 30 controls without TB who had similar CD4+ T cell counts and viral loads at the time of starting cART. We compared the rate of CD4+ T cell increase for 5 years after cART. The time to CD4+ T cell increase >250 cells/mm3 was significantly slower in HIV-TB-coinfected patients (p=0.015, by log rank test). HIV-TB-coinfected patients had significantly lower median CD4+ T cell counts at 5 years after cART (p=0.048). The difference in CD4+ T cell increase was observed only during the first 6 months after cART initiation (p=0.002). These data suggest that TB slows the rate of CD4+ T cell recovery at an early period after cART. The effects of TB on the long-term immunity of HIV-infected patients should be further evaluated.
doi:10.1089/aid.2012.0192
PMCID: PMC3552174  PMID: 22881387
9.  Antiretroviral Treatment as Prevention: Impact of the ‘Test and Treat’ Strategy on the Tuberculosis Epidemic 
Current HIV Research  2011;9(6):383-392.
Antiretroviral therapy (ART) has been remarkably effective in ameliorating Human Immunodeficiency Virus (HIV)-associated morbidity and mortality. The rapid decline in viral load during ART also presents an opportunity to develop a “treatment as prevention” strategy in order to reduce HIV transmission at a population level. Modelling exercises have demonstrated that for this strategy to be effective, early initiation of ART with high coverage of the HIV-infected population will be required. The HIV epidemic has fueled a resurgence of tuberculosis (TB) particularly in sub-Saharan Africa and widespread early initiation of ART could also impact this epidemic via several mechanisms. The proportion of patients with low CD4 cell counts who are at high risk of TB disease from progression of both latent and new TB infection would be greatly reduced. Entry into a life-long ART program provides an ongoing opportunity for intensified TB case finding among the HIV-infected population. Regular screening for HIV infection also presents an opportunity for intensified TB case finding in the general population. The combined effect of reduced progression of infection to disease and intensified case finding could reduce the overall prevalence of infectious TB, thereby further decreasing TB transmission. In addition, decreasing prevalence of HIV infection would reduce the TB-susceptible pool within the population. The ‘test and treat’ strategy therefore has potential to reduce the TB risk at both an individual and a population level. In this paper we explore the expected “TB dividend” of wider access to ART and also explore the potential of the “test and treat” strategy to impact on TB transmission, particularly in the heavily burdened setting of sub-Saharan Africa.
doi:10.2174/157016211798038524
PMCID: PMC3537121  PMID: 21999773
Communicable disease control; HAART; highly active antiretroviral therapy; HIV prevention; tuberculosis prevention
10.  Initiation of Antiretroviral Therapy in HIV-Infected Tuberculosis Patients in Rural Kenya: An Observational Study 
Background
Recent randomised controlled trials have examined the issue of when to start antiretroviral therapy in HIV-infected patients with tuberculosis (TB). There is, however, little information on the effect of timing of antiretroviral therapy (ART) initiation on outcomes in real-life, non-clinical trial, rural settings in sub-Saharan Africa.
Methods
We conducted an observational cohort study of all HIV-infected TB patients presenting to a rural hospital in Kenya between 2005 and 2009. We analysed the association between timing of initiation of ART and mortality, using a Cox regression survival analysis, adjusted for measured confounders.
Results
404 antiretroviral-naïve HIV/TB co-infected patients were included in the study. Initiation of ART during the first 8 weeks of TB treatment (early group) was not associated with changes in mortality at one year compared to those who initiated ART after 8 weeks (late group) [Hazard Ratio (HR) = 0.74 (Confidence Interval (CI) 0.33 – 1.64, p=0.46]. In those with baseline CD4 counts ≤50 cells/μl, there was a significant reduction in mortality in the early group compared to the late group (HR= 0.20, 95% CI 0.042 - 0.99, p=0.049). In patients with a CD4 count >50 cells/μl there was no significant difference between early and late groups (HR 1.79 95% CI 0.64- 5.03, P=0.27)
Conclusions
We found that in HIV/TB co-infected patients in rural Kenya, early ART initiation (within 8 weeks) was associated with reduced mortality in those with CD4 counts ≤50 cells/μl. In patients with CD4 counts >50 cells/μl there was no association seen between timing of ART and mortality.
doi:10.1111/tmi.12110
PMCID: PMC3999513  PMID: 23590229
11.  Intensive Tuberculosis Screening for HIV-Infected Patients Starting ART in Durban, South Africa 
Background
The World Health Organization (WHO) recommends cough as the trigger for tuberculosis (TB) screening in HIV-infected patients, with acid fast bacillus (AFB) smear as the initial diagnostic test. Our objective was to assess the yield and cost of a more intensive TB screening in HIV-infected patients starting antiretroviral therapy (ART) in Durban, South Africa.
Methods
We prospectively enrolled adults, regardless of TB signs/symptoms, undergoing pre-ART training from May ‘07–May ‘08. Following symptom screen, patients expectorated sputum for AFB smear, TB polymerase chain reaction (PCR), and mycobacterial culture. Sensitivity and specificity of different symptoms and tests, alone and in combination, were compared to a gold standard of 6-week TB culture results. Program costs included personnel, materials and cultures.
Results
Of 1,035 subjects, 487 (59%) were female; median CD4 count was 100/μl. Two-hundred and ten (20%) were receiving TB treatment and were excluded. Of the remaining 825 subjects, 158 (19%) had positive sputum cultures, of whom 14 (9%) had a positive AFB smear and 82 (52%) reported cough. The combination of cough, other symptoms, AFB smear, and chest x-ray had 93% (CI 88–97%) sensitivity and 15% (CI 13–18%) specificity. The incremental cost of intensive screening including culture was $360/additional TB case identified.
Conclusions
Nearly 20% of patients starting ART in Durban, South Africa had undiagnosed, culture-positive pulmonary TB. Despite WHO recommendations, neither cough nor AFB smear were adequately sensitive for screening. TB sputum cultures should be performed before ART initiation, regardless of symptoms, in areas of high HIV/TB prevalence.
doi:10.1086/656282
PMCID: PMC3204934  PMID: 20735240
Tuberculosis; South Africa; WHO guidelines
12.  Effectiveness of Early Antiretroviral Therapy Initiation to Improve Survival among HIV-Infected Adults with Tuberculosis: A Retrospective Cohort Study 
PLoS Medicine  2011;8(5):e1001029.
Molly Franke, Megan Murray, and colleagues report that early cART reduces mortality among HIV-infected adults with tuberculosis and improves retention in care, regardless of CD4 count.
Background
Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting.
Methods and Findings
We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count≤350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small.
Conclusions
Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
HIV infection has exacerbated the global tuberculosis (TB) epidemic, especially in sub-Saharan Africa, in which in some countries, 70% of people with TB are currently also HIV positive—a condition commonly described as HIV/TB co-infection. The management of patients with HIV/TB co-infection is a major public health concern.
There is relatively little good evidence on the best time to initiate combination antiretroviral therapy (cART) in adults with HIV/TB co-infection. Clinicians sometimes defer cART in individuals initiating TB treatment because of concerns about complications (such as immune reconstitution inflammatory syndrome) and the risk of reduced adherence if patients have to remember to take two sets of pills. However, starting cART later in those patients who are infected with both HIV and TB can result in potentially avoidable deaths during therapy.
Why Was This Study Done?
Several randomized control trials (RCTs) have been carried out, and the results of three of these studies suggest that, among individuals with severe immune suppression, early initiation of cART (two to four weeks after the start of TB treatment) leads to better survival than later ART initiation (two to three months after the start of TB treatment). These results were reported in abstract form, but the full papers have not yet been published. One problem with RCTs is that they are carried out under controlled conditions that might not represent well the conditions in varied settings around the world. Therefore, observational studies that examine how effective a treatment is in routine clinical conditions can provide information that complements that obtained during clinical trials. In this study, the researchers aimed to confirm the results from RCTs among a cohort of adult patients with HIV/TB co-infection in Rwanda, diagnosed under routine program conditions and using routinely collected clinical data. The researchers also wanted to investigate whether early cART initiation reduced the risk of other adverse outcomes, including treatment default and loss to follow-up.
What Did the Researchers Do and Find?
The researchers retrospectively reviewed the charts and other program records of 308 patients with HIV, who had CD4 counts≤350 cells/µl, were aged 15 years or more, had never previously taken cART, and received their first TB treatment at one of five cART sites (two urban, three rural) in Rwanda between January 2004 and February 2007. Using this method, the researchers collected baseline demographic and clinical variables and relevant clinical follow-up data. They then used this data to estimate the effect of cART on survival by using sophisticated statistical models that calculated the effects of initiating cART at 15, 30, 60, or 180 d after the start of TB treatment or not at all.
The researchers then conducted a further analysis to assess combined outcomes of (1) death, default, lost to follow-up, and (2) death, hospitalization due to any cause, or occurrence of severe opportunistic infections, such as Kaposi's sarcoma. The researchers used the resulting multivariable model to estimate survival probabilities for each individual, based on his/her baseline characteristics.
The researchers found that when they set their model to first CD4 cell counts of 50 and 100 cells/µl, and starting cART at day 15, mean survival probabilities at two years were 0.82 and 0.86, respectively, statistically significantly higher than the survival probabilities calculated for each of the other treatment strategies, where cART was started later. They observed a similar pattern for the combined outcome of death, hospitalization, or serious opportunistic infection In addition, two-year outcomes for death or lost to follow-up were also improved with early cART, regardless of CD4 count at treatment initiation.
What Do These Findings Mean?
These findings show that in a real world program setting, starting cART 15 d after the start of TB treatment is more beneficial (measured by differences in survival probabilities) among patients with HIV/TB co-infection who have CD4 cell counts≤100 cells/µl than starting later. Early cART initiation may also increase retention in care for all individuals with CD4 cell counts≤350 cells/µl.
As the outcomes of this modeling study are based on data from a retrospective observational study, the biases associated with use of these data must be carefully addressed. However, the results support the recommendation of cART initiation after 15 d of TB treatment for patients with CD4 cell counts≤100 cells/µl and can be used as an advocacy base for TB treatment to be used as an opportunity to refer and retain HIV-infected individuals in care, regardless of CD4 cell count.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001029.
Information is available on HIV/TB co-infection from the World Health Organization, the US Centers for Disease Control and Prevention, and the International AIDS Society
doi:10.1371/journal.pmed.1001029
PMCID: PMC3086874  PMID: 21559327
13.  Low Uptake of Antiretroviral Therapy and High Mortality After Tuberculosis or Opportunistic Infection in KwaZulu-Natal, South Africa 
Objectives
A prospective cohort study was conducted among HIV-infected inpatients with tuberculosis or other opportunistic infection (OI) in South Africa to estimate subsequent antiretroviral therapy (ART) uptake and survival.
Methods
Logistic regression modeling explored associations between baseline characteristics and starting ART, and ART exposure adjusted incidence of death was estimated over 6 months of follow-up.
Results
Among 49 participants enrolled, median CD4 cell count at hospital discharge was 42 cells/mm3, and the most common presenting OI were tuberculosis (76 %), Pneumocystis pneumonia (8%), chronic diarrhea (8%), cryptococcal meningitis (6%), and Toxoplasmosis gondii (4%). By 6 months, only 20 (45%)had initiated ART, and 4 (8%) were lost to follow-up. ART uptake was independently associated with previous use of traditional medicine (OR 7.2; 95% CI 1.4 – 55.1) and with less advanced HIV infection (baseline CD4 count (per 50 cells/mm3increase OR 1.4; 95% CI 0.9–2.2). A total of 14 (31%)died before initiating ART; the monthly incidence of death did not decrease over the 6 month interval.
Conclusion
High mortality observed within the 6 months following hospitalization with tuberculosis or other acute OI argue that mechanisms are needed to expedite ART for patients after AIDS-defining illness.
PMCID: PMC3207641  PMID: 20550776
14.  The cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy in South Africa: a model-based analysis 
AIDS (London, England)  2012;26(8):987-995.
Background
In settings with high tuberculosis prevalence, 15–30% of HIV-infected individuals initiating antiretroviral therapy (ART) have undiagnosed tuberculosis. Such patients are usually screened by symptoms and sputum smear, which have poor sensitivity.
Objective
To project the clinical and economic outcomes of using Xpert MTB/RIF(Xpert), a rapid tuberculosis/rifampicin-resistance diagnostic, to screen individuals initiating ART.
Design
We used a microsimulation model to evaluate the clinical impact and cost-effectiveness of alternative TB screening modalities -in all patients or only symptomatic patients - for hypothetical cohorts of individuals initiating ART in South Africa (mean CD4 171/μL; tuberculosis prevalence 22%). We simulated no active screening and four diagnostic strategies: 1) smear microscopy (sensitivity 23%); 2) smear and culture (sensitivity, 100%); 3) one Xpert sample (sensitivity in smear-negative tuberculosis: 43%); 4) two Xpert samples (sensitivity in smear-negative tuberculosis: 62%). Outcomes included projected life expectancy, lifetime costs (2010 USD), and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs <$7,100 (South African gross domestic product per capita) were considered very cost-effective.
Results
Compared with no screening, life expectancy in tuberculosis-infected patients increased by 1.6 months using smear in symptomatic patients and by 6.6 months with 2 Xpert samples in all patients. At 22% tuberculosis prevalence, the ICER of smear for all patients was $2,800/year of life saved (YLS), and of Xpert (2 samples) for all patients was $5,100/YLS. Strategies involving one Xpert sample or symptom screening were less efficient.
Conclusions
Model-based analysis suggests that screening all individuals initiating ART in South Africa with two Xpert samples is very cost-effective.
doi:10.1097/QAD.0b013e3283522d47
PMCID: PMC3517815  PMID: 22333751
tuberculosis; HIV; cost-effectiveness; diagnostics; antiretroviral therapy
15.  Immunologic Markers as Predictors of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV and Tuberculosis Coinfected Persons in Thailand 
AIDS Research and Human Retroviruses  2009;25(11):1083-1089.
Abstract
This study analyzes immunologic markers to predict and diagnose tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV and TB coinfected adults who initiated antiretroviral therapy (ART) in Thailand. T helper 1 cytokines interleukin (IL)-2, IL-12, and interferon-gamma (IFN-γ) levels in response to PPD and RD1 antigens were assessed prior to ART, at weeks 6, 12, and 24 of treatment, and at time of TB-IRIS. Of 126 subjects, 22 (17.5%) developed TB-IRIS; 14 (64%) subjects received steroid treatment and 3 (14%) received NSAIDs; none of the subjects died. Median interval between ART initiation and TB-IRIS development was 14 days. IFN-γ, IL-2, and IL-12 responses did not differ between TB-IRIS and no TB-IRIS subjects (p > 0.05). More research into the immunopathogenesis of TB-IRIS and diagnostic potential of cytokine markers is warranted.
doi:10.1089/aid.2009.0055
PMCID: PMC2828258  PMID: 19886838
16.  Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors and prevention strategies 
Objective
To determine tuberculosis (TB) incidence rates and risk factors among individuals receiving antiretroviral treatment (ART).
Design
Observational cohort in Johannesburg, South Africa.
Methods
Incident TB was classified as early (<6 months of ART) or late (>6 months of ART) incident TB. CD4 cell counts, viral load (VL), body mass index (BMI) and hemoglobin were measured 6-monthly. Hazard ratios for factors associated with early and late incident TB were assessed using Cox proportional hazards regression.
Results
During 13,416 person-years (py) follow-up, 501 TB cases occurred among 7,536 individuals, corresponding to a 10% risk in the first four years of ART, and an overall incidence rate of 4.2 cases/100 py. The highest incidence rate (21.7 /100 py) was observed in the first 3 months of ART among people with CD4 count below 50 cells/mm3. Low baseline CD4 count, anemia, and low BMI were the strongest risk factor for early incident TB. Low updated CD4 count, low updated BMI, anemia, and high VL on ART were strong risk factors for late incident TB.
Conclusions
Severity of HIV disease and unfavorable response to ART are associated with early and late incident TB, respectively. Early ART initiation and intensified TB screening at ART initiation are crucial to reduce incident TB.
doi:10.1097/QAI.0b013e3181f9fb39
PMCID: PMC3319435  PMID: 20926954
tuberculosis; TB; antiretroviral treatment; incidence; risk factors; South Africa
17.  Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa 
AIDS (London, England)  2009;23(13):1717-1725.
Objective
To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART).
Design
Observational community-based ART cohort in South Africa.
Methods
TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models.
Results
Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/µl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/µl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk.
Conclusion
Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/µl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/µl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/µl.
doi:10.1097/QAD.0b013e32832d3b6d
PMCID: PMC3801095  PMID: 19461502
Africa; antiretroviral; CD4 cell; HIV; immune reconstitution; resource-limited country; tuberculosis
18.  Time to Initiation of Antiretroviral Therapy Among Patients With HIV-Associated Tuberculosis in Cape Town, South Africa 
We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n=1433; median CD4 count 71 cells/μL, IQR,32-132) attending three South African township ART services between 2002-2008. The overall median delay was 2.66 months (IQR,1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7% and 51.1% of patients started ART within 2, 4 and 8 weeks of TB treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.
doi:10.1097/QAI.0b013e3182199ee9
PMCID: PMC3717455  PMID: 21436714
tuberculosis; antiretroviral; timing; delay; Africa
19.  Are routine tuberculosis programme data suitable to report on antiretroviral therapy use of HIV-infected tuberculosis patients? 
BMC Research Notes  2013;6:23.
Background
Antiretroviral therapy (ART) is lifesaving for HIV-infected tuberculosis (TB) patients. ART-use by these patients lag behind compared to HIV-testing and co-trimoxazole preventive therapy. TB programmes provide the data on ART-use by HIV-infected TB patients, however often the HIV services provide the ART. We evaluated whether the data on ART-use in the TB register were complete and correct. The timing of ART initiation was evaluated to assess whether reporting on ART-use could have happened with the TB case finding reporting. We collected data on TB treatment, HIV testing and ART for adult TB cases in 2007 from three TB clinics in Manica Province, Mozambique. These data on use of ART from TB registers were compared with those from the HIV services.
Findings
Of 628 patients included, 504 (81%) were tested and of these 356 (71%) were HIV-infected. Of the co-infected patients, 81% registered with the HIV services in the same facility. The TB register was correct on ART-use in 73% of co-infected cases and complete in 74%. Information on ART-use could have been reported with the TB case finding reports in 56% of co-infected patients.
Conclusion
The TB register is reasonably correct and complete on ART-use. However, the HIV patient record seems a much better source to provide this information. Reporting on ART-use at the end of the quarter in which TB treatment starts provides the programme with timely but incomplete information. A more complete but less timely picture is available after a year.
doi:10.1186/1756-0500-6-23
PMCID: PMC3556319  PMID: 23331952
Africa; Routine programme data; Tuberculosis; HIV
20.  Immune reconstitution inflammatory syndrome presenting as chylothorax in a patient with HIV and Mycobacterium tuberculosis coinfection: a case report 
BMC Infectious Diseases  2010;10:321.
Background
Patients with human immunodeficiency virus (HIV) infection are at risk for Mycobacterium tuberculosis (TB) coinfection. The advent of antiretroviral therapy restores immunity in HIV-infected patients, but predisposes patients to immune reconstitution inflammatory syndrome (IRIS).
Case Presentation
A 25-year-old HIV-infected male presented with fever, productive cough, and body weight loss for 2 months. His CD4 cell count was 11 cells/μl and HIV-1 viral load was 315,939 copies/ml. Antituberculosis therapy was initiated after the diagnosis of pulmonary TB. One week after antituberculosis therapy, antiretroviral therapy was started. However, multiple mediastinal lymphadenopathies and chylothorax developed. Adequate drainage of the chylothorax, suspension of antiretroviral therapy, and continued antituberculosis therapy resulted in successful treatment and good outcome.
Conclusions
Chylothorax is a rare manifestation of TB-associated IRIS in HIV-infected patients. Careful monitoring for development of IRIS during treatment of HIV-TB coinfection is essential to minimize the associated morbidity and mortality.
doi:10.1186/1471-2334-10-321
PMCID: PMC2988055  PMID: 21059235
21.  Provider experiences of the implementation of a new tuberculosis treatment programme: A qualitative study using the normalisation process model 
Background
Tuberculosis (TB) is a major contributor to the global burden of disease. In many settings, including South Africa, treatment outcomes remain poor. In contrast, many antiretroviral treatment (ART) programmes are achieving high levels of adherence and good outcomes. The ART programme model for maintaining treatment adherence may therefore hold promise for TB treatment. Changing treatment models, however, requires an assessment of how staff receive the new model, as they are responsible for programme implementation. Using the normalization process model as an analytic framework, this paper aims to explore staff perceptions of a new TB treatment programme modelled on the ART treatment programme.
Methods
A qualitative approach was used. Interviews and focus group discussions were conducted with clinic staff from five intervention clinics. Data were analysed initially using qualitative content analysis. The resulting categories were then organised under the constructs of the normalization process model.
Results
Staff recounted a number of challenges with implementing the programme. Interviews and focus group discussions identified factors relating to the main categories of the normalization process model. The key issues hindering the normalisation of the programme within clinics related to the interactional workability, relational integration and skill-set workability constructs of the model. These included hierarchical relationships, teamwork, training needs and insufficient internalisation by staff of the empowerment approach included in the programme. Logistical and management issues also impacted negatively on the normalization of the programme at the clinics.
Conclusion
The normalization process model assisted in categorising the challenges experienced during implementation of the intervention. The results suggest that issues remain that need to be resolved before the programme is implemented more widely. Considerable work is needed in order to embed the intervention in routine clinic practice.
doi:10.1186/1472-6963-11-275
PMCID: PMC3215962  PMID: 22004533
22.  Duration of Anti-Tuberculosis Therapy and Timing of Antiretroviral Therapy Initiation: Association with Mortality in HIV-Related Tuberculosis 
PLoS ONE  2013;8(9):e74057.
Background
Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear.
Methods
We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended.
Results
Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm3, 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti-tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007).
Conclusions
The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated.
doi:10.1371/journal.pone.0074057
PMCID: PMC3774609  PMID: 24066096
23.  Randomized Controlled Trial of Trained Patient-Nominated Treatment Supporters Providing Partial Directly Observed Antiretroviral Therapy 
AIDS (London, England)  2010;24(9):1273-1280.
Background
Directly observed therapy (DOT) for antiretroviral therapy (ART) may improve adherence, but there are limited data on its clinical effectiveness.
Methods
Adult patients initiating ART in a public clinic in Cape Town, South Africa, were randomized to treatment-supporter DOT-ART or self-administered ART. DOT-ART patients and supporters received baseline and follow up training and monitoring. The primary endpoints were the proportion of patients with HIV viral load (VL) <400copies/mL and change in CD4 cell counts at 12 and 24 months.
Results
274 patients enrolled (137 in each arm) and baseline characteristics were similar for both arms. The study was stopped early for futility by an independent Data and Safety Monitoring Board. In an intention-to-treat analysis, the proportions of patients with VL <400 copies/mL at 12 months were 72.8% in the DOT-ART arm and 68.4% in the Self-ART arm (p= 0.42). DOT-ART patients had greater median CD4 cell count (cells/µL) increases at 6 months (148 [IQR 84-222] vs. 111 [IQR 44-196]; p= 0.02) but similar results at all other time-points. Survival was significantly better in the DOT-ART arm (N=9, 6.6%) than in the Self-ART arm (N=21, 15.3%; log-rank p = 0.02). In Cox regression analysis, mortality was independently associated with study arm (DOT vs. self-ART; HR 0.38, 95% CI 0.17–0.86).
Conclusion
DOT-ART showed no effect on virologic outcomes but was associated with greater CD4 cell count increases at 6 month follow-up. Survival was significantly better for DOT-ART compared to Self-ART, but this was not explained by improved virologic or immunologic outcomes.
doi:10.1097/QAD.0b013e328339e20e
PMCID: PMC2888722  PMID: 20453627
HIV-1; antiretroviral therapy; adherence; randomized controlled trial; treatment social supporter; directly observed therapy
24.  Development of Dual-class Antiretroviral Drug Resistance in a Child Coinfected with HIV and Tuberculosis: A Case Report from KwaZulu-Natal, South Africa 
Journal of Tropical Pediatrics  2008;55(1):60-62.
The treatment of concurrent HIV and tuberculosis (TB) in children <3 years of age has not been well-studied and is complicated by potential drug–drug interactions. The recommended antiretroviral therapy (ART) in coinfected children in South Africa consists of full-strength ritonavir, lamivudine and stavudine. We report on a child initiated on this regimen, during concurrent TB treatment, who promptly developed an adverse reaction, virologic failure and dual-class antiretroviral drug resistance, compromising subsequent salvage ART.
doi:10.1093/tropej/fmn074
PMCID: PMC2734312  PMID: 18786985
25.  Natural Killer cell activation distinguishes M. tuberculosis-mediated Immune reconstitution syndrome (IRIS) from chronic HIV and HIV-MTB co-infection 
Background
With increased access to antiretroviral treatment (ART), Immune Reconstitution Inflammatory Syndrome (IRIS) in Mycobacterium tuberculosis (MTB)-infected populations remains a clinical challenge. We studied a cross-sectional cohort of HIV-infected subjects in Johannesburg (South Africa) to help define the immune correlates that best distinguish IRIS from ongoing MTB cases.
Methods
We studied HIV+ subjects developing MTB-related unmasking IRIS (u-TB-IRIS) after ART initiation; control groups were HIV subjects and HIV-TB co-infected subjects with comparable ART treatment. Testing was conducted with whole blood-based 4-color flow cytometry and plasma-based Luminex cytokine assessment.
Results
NK cell activation, C-reactive protein and IL-8 serum concentration were significantly higher in u-TB-IRIS subjects as compared to both control groups. In addition, all MTB co-infected subjects, independent of clinical presentation, had higher neutrophils and T cell activation, together with lower lymphocytes, CD4+ T cell and myeloid DC counts. Using conditional inference tree analysis we show that elevated NK cell activation in combination with lymphocyte count characterizes the immunological profile of u-TB-IRIS.
Conclusions
Our results support a role for innate immune effectors in the immunopathogenesis of unmasking MTB-related IRIS, and identify new immune parameters defining this pathology.
doi:10.1097/QAI.0b013e31822e0d15
PMCID: PMC3196770  PMID: 21826013
Mycobacterium tuberculosis; IRIS; HIV; immune reconstitution; natural killer cells; CD69

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