Bulletin of the World Health Organization

Timing of antiretroviral therapy in Cambodian hospital after diagnosis of tuberculosis: impact of revised WHO guidelines

Kimcheng Choun a, Reaksmey Pe a, Sopheak Thai a, Natalie Lorent b, Lutgarde Lynen b & Johan van Griensven b

a. Sihanouk Hospital Centre of Hope, St. 134, Sangkat Vealvong, Khan 7 Makara, Phnom Penh, Cambodia.
b. Institute of Tropical Medicine, Antwerp, Belgium.

Correspondence to Johan van Griensven (e-mail: jvangriensven@itg.be).

(Submitted: 07 August 2012 – Revised version received: 14 November 2012 – Accepted: 16 November 2012 – Published online: 12 December 2012.)

Bulletin of the World Health Organization 2013;91:195-206. doi: 10.2471/BLT.12.111153

Introduction

Tuberculosis remains one of the major causes of death in patients infected with the human immunodeficiency virus (HIV) in resource-limited settings.1 Initiating antiretroviral therapy (ART) during the treatment of tuberculosis has been shown to reduce mortality across a wide range of CD4+ T-lymphocyte (CD4+ cell) counts better than waiting until completion of antituberculosis treatment.2 However, in programmes in low-resource settings, ART uptake is often poor or treatment is delayed.38 The 2010 revision of the World Health Organization (WHO) guidelines for ART in low-resource settings, which recommend ART in HIV-positive patients with tuberculosis, irrespective of CD4+ cell count, has been a major step forward. According to these guidelines ART should be initiated as soon as the antituberculosis therapy is tolerated, which could be as early as two weeks but ideally not more than eight weeks after the start of treatment.9 These revised guidelines were followed by the publication of three clinical trials comparing early and late ART initiation (2–4 weeks versus 8–12 weeks after commencing antituberculosis treatment).1012 Overall, these studies demonstrated that early ART can be safely implemented and that it is associated with a survival benefit mainly concentrated among individuals with baseline CD4+ cell counts of < 50 cells/µL.13

Several factors could preclude the implementation of these revised guidelines in routine clinical settings in resource-limited areas. First, good integration of tuberculosis and HIV care programmes, which has proved challenging, is required.1418 Operational issues or non-compliance with the guidelines at the level of the health care system or provider could delay ART initiation.19 Second, the rates of early death and loss to follow-up before ART initiation are usually higher in programme settings than in controlled study settings.6,2025 Third, early initiation in routine care may be delayed by the management of co-morbid conditions and opportunistic infections.

Several recent studies have reported the impact of integrating tuberculosis and HIV services on improved and accelerated ART uptake.2636 However, there has been no formal evaluation of the operational feasibility and impact of the revised WHO guidelines on the timing of ART initiation within routine clinical settings. The main objective of this study was to assess the change in time to ART initiation following the implementation of the 2010 WHO ART guidelines in a programmatic setting in a resource-limited area. The secondary objective was to monitor trends in HIV infection treatment outcomes (retention on ART) and toxicity-driven antiretroviral drug substitutions. In this operational study, no reliable data on the occurrence of the immune reconstitution inflammatory syndrome could be obtained.

Methods

Study design and population

In March 2003, Sihanouk Hospital Centre of Hope started providing comprehensive HIV care free of charge in Phnom Penh, Cambodia, as part of the national ART programme. Patients presenting at this nongovernmental hospital come from both rural and urban areas (around 50% each) and are almost universally poor. We conducted a retrospective cohort study with a before–after design. We included in the study all ART-naïve HIV-positive adults who initiated antituberculosis treatment as inpatients or outpatients over the 18 months that preceded and the 18 months that followed the implementation of the 2010 WHO guidelines in June 2010. The pre-implementation period extended from 1 December 2008 to 31 May 2010 and the post-implementation period, from 1 June 2010 to 30 November 2011. Before June 2010 the hospital had followed the 2006 WHO guidelines.

Organization of tuberculosis and HIV care

The tuberculosis and HIV care clinics were located within close vicinity of each other in the hospital. Over 3000 adult patients on ART were in follow-up at the HIV clinic; an average of around 1400 individuals were screened annually for tuberculosis at the tuberculosis clinic. All patients with HIV infection were routinely screened for tuberculosis, and testing for HIV was proposed to all cases diagnosed with tuberculosis. Details of the organizational setup are given in Box 1 and Fig. 1.

Box 1. Overview of care activities at the tuberculosis and HIV care clinics

Tuberculosis clinic

  • Tuberculosis diagnostic workup (by tuberculosis care physician) of cases referred with possible tuberculosis
  • Immediate referral of tuberculosis cases for HIV testing and same-day enrolment in HIV care if HIV-positive
  • Tuberculosis daily observed treatment and support; monitoring of side-effects
  • Recording of detailed tuberculosis information (screening, diagnosis, treatment)

HIV clinic

  • Tuberculosis screening (by HIV care physician)
  • HIV care programme enrolment (sputum smear microscopy, additional tests as indicated)
  • Tuberculosis symptom screening at every clinical encounter
  • Pre-ART initiation (sputum smear microscopy and routine chest X-ray)
  • IPT if tuberculosis ruled out (since March 2011)
  • Diagnostic work-up if tuberculosis suspected in HIV-positive individuals (sputum collected at tuberculosis clinic)
  • Tuberculosis treatment decision (HIV care physician with input from tuberculosis physician as required)
  • Electronic recording of clinical information (including on tuberculosis) for all HIV-positive individuals

Factors enhancing coordination/integration of tuberculosis and HIV activities

  • Localized in close vicinity in the same hospital and within the same department
  • Joint multidisciplinary meetings (logistical, operational, medical topics)
  • Joint staff trainings
  • Well defined role of tuberculosis and HIV clinic staff in tuberculosis- and HIV-related activities
  • Key information on HIV infection and tuberculosis cases collected in a single database

ART, antiretroviral therapy; HIV, human immunodeficiency virus; IPT, isoniazid preventive therapy

Fig. 1. Organization of tuberculosis and HIV care activities and initiation and monitoring of antiretroviral therapy (ART), Cambodia, December 2008 to November 2011
Fig. 1. Organization of tuberculosis and HIV care activities and initiation and monitoring of antiretroviral therapy (ART), Cambodia, December 2008 to November 2011
AFB, acid-fast bacilli; AZT, zidovudine; D4T, stavudine; EFV, efavirenz; FBC, full blood count; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 3TC, lamivudine; LFT, liver function tests; M, month; OI, opportunistic infection; W, week; WHO, World Health Organization.

Tuberculosis screening and diagnosis

The tools for tuberculosis diagnosis available in our setting included microscopy to check for acid-fast bacilli in sputum smears and lymph node fine needle aspirates, chest radiography and abdominal ultrasound (Box 1 and Fig. 1). Tuberculosis screening and diagnostic algorithms recommended by the WHO and the national tuberculosis programme were used throughout the study period.37,38 Tuberculosis was diagnosed according to WHO criteria for smear-positive pulmonary tuberculosis, smear-negative pulmonary tuberculosis or extrapulmonary tuberculosis.37,38

All patients diagnosed with tuberculosis were evaluated for ART eligibility. As explained earlier, up to May 2010, the 2006 WHO ART guidelines were used;39 following a revision of the Cambodian national guidelines the 2010 WHO ART guidelines were implemented beginning on 1 June 2010. Clinicians were instructed to initiate ART early on, irrespective of CD4+ cell count, and ideally two weeks after initiation of antituberculosis treatment.9 Before implementation, the rationale and required changes in patient flow and organization were discussed with the entire team in charge of tuberculosis and HIV services (Box 2).

Box 2. Implementation of early initiation of antiretroviral therapy (ART) in patients with tuberculosis and HIV co-infection: organizational aspects

Communication: platforms for discussion, planning and dissemination of information (general)

  • Weekly medical department meeting (tuberculosis and HIV physicians)
  • Monthly multidisciplinary meeting of key HIV and tuberculosis care staff to discuss logistical and managerial issues
  • Monthly multidisciplinary operational meeting with the entire HIV and tuberculosis care team
  • Daily educational activities for HIV patients attending the HIV clinic

Preparation of implementation

  • Required changes in patient flow discussed during above-mentioned meetings: key changes consisted of more rapid pre-ART counselling and fast-tracking for ART initiation
  • No concurrent changes in tuberculosis case-finding strategies or tuberculosis and HIV care clinic organizational set-up (staffing, HIV/tuberculosis service delivery model) were made
  • Starting date of implementation fixed

Monitoring

  • Within each service, supervisors monitored adherence to the implementation during their routine (clinical) work as part of their continuous monitoring of all guidelines and practices
  • Operational challenges with implementation could be raised by the staff during above-mentioned team meetings

HIV, human immunodeficiency virus

Antiretroviral initiation and monitoring

Programme details, including toxicity monitoring and outcome data of the ART programme in the Sihanouk Hospital Centre of Hope have been published before (Fig. 1).21,4043 All medical care was provided by physicians, supported by a team of nurses and adherence counsellors. From early 2010 on, patient tracing was reinforced by systematically telephoning patients not presenting at their scheduled visit. This resulted in gradual improvements in outcome ascertainment over the study period. Patients not presenting at the hospital for a period of 6 months without additional information were considered lost to follow-up.

Data collection

At the onset of the ART programme, structured clinical records, data collection tools and a database were developed.21 Clinical, laboratory and treatment data, including data on tuberculosis diagnosis and treatment, were collected and stored electronically every day. Physicians were trained to conduct standardized patient assessment using the hospital guidelines and protocols. Quality control of the stored data was performed at regular intervals. For this study, data were extracted from this database. Data were cross-checked against HIV clinical records and tuberculosis registers.

Statistical analysis

The main outcome was the time from the diagnosis of tuberculosis to ART initiation and the probability of starting ART within the 8-week period immediately following the diagnosis. Secondary outcomes included overall programme retention (i.e. the proportion of patients retained on ART) six months after the diagnosis of tuberculosis and the proportion with toxicity-related antiretroviral drug substitution six months after ART initiation.

Baseline patient characteristics before and after implementation were described and compared using χ2 or Fisher’s exact tests for categorical variables and the Wilcoxon rank-sum test for continuous variables. Follow-up time was censored at the earliest of the following: ART initiation, death, loss to follow-up, transfer-out, or end of study period. Among individuals initiating ART, we calculated the median and interquartile range (IQR) of the time in weeks from the diagnosis of tuberculosis to ART initiation before and after implementation of the new WHO guidelines, stratified by baseline CD4+ cell count. We compared pre- and post-implementation values using the Wilcoxon test. To visualize the effect of guideline implementation, we calculated the median ART delay per quartile and plotted it on a graph (Fig. 2). We used Kaplan–Meier methods to estimate the cumulative incidence of ART initiation at 2, 4 and 8 weeks after the diagnosis of tuberculosis among those initiating ART. In a secondary analysis, we calculated the overall probability of initiation of ART among all individuals diagnosed with tuberculosis, whether or not they ever initiated ART. In case of competing risks (ART initiation precluded by death), standard survival methods can provide biased estimates.44,45 Consequently, we used a competing risks proportional hazards regression model to identify independent factors associated with probability of ART initiation.44,45 We modelled the effect of the implementation of revised WHO guidelines on time to ART initiation after a diagnosis of tuberculosis was modelled over three time periods: < 2 weeks, 2–6 weeks and > 6 weeks after the diagnosis. In addition, the following factors were considered for inclusion in the model: age, sex, type of tuberculosis (extrapulmonary or pulmonary), point of entry into care (HIV or tuberculosis care programme) and CD4+ cell count when tuberculosis was diagnosed. Starting from the full model, a stepwise selection process was performed. Associations in the model were reported as subhazard ratios (sHR). The proportional-hazards assumption was tested graphically and formally using Schoenfeld residuals. The cumulative incidence of starting ART, with death before ART (pre-ART death) as a competing risk, was calculated as well. In sensitivity analysis, we treated a combined end-point consisting of pre-ART death and loss to follow-up as a competing event (i.e. we assumed that individuals who were lost to follow-up before initiating ART had died).

Fig. 2. Evolution of time to initiation of antiretroviral therapy (ART), pre- and post-implementation of the 2010 WHO guidelines, December 2008 to November 2011
Fig. 2. Evolution of time to initiation of antiretroviral therapy (ART), pre- and post-implementation of the 2010 WHO guidelines, December 2008 to November 2011
IPT, isoniazid preventive therapy; WHO, World Health Organization.

We performed logistic regression to look for an association between implementation of the revised WHO guidelines and secondary outcomes. Additional covariates such as sex, age, body weight at the time when tuberculosis was diagnosed, type of tuberculosis, and point of entry into care were considered potential confounders for inclusion. For retention on ART as outcome, we selected a priori for inclusion in the model the CD4+ cell count and body weight at the time of the diagnosis of tuberculosis; for drug substitution as outcome, we selected a priori sex, age and CD4+ cell count at the time of the diagnosis of tuberculosis. We analysed the data using STATA version 11 (STATACorp LP, College Station, United States of America). The level of significance was set at P < 0.05.

Ethical issues

Since the launch of the HIV care programme, clinical data have been routinely collected for purposes of programme monitoring and evaluation and research activities. Patients were requested to give written informed consent to store and use the data. The data collection and informed consent procedures were approved by the Institutional Review Board of the Institute of Tropical Medicine, Antwerp, Belgium, and the Institutional Review Board of the Sihanouk Hospital Centre of Hope.

Results

Patient characteristics

The post-implementation group consisted of 190 patients. Before revised guideline implementation, 262 patients with tuberculosis and HIV co-infection were identified. Both groups were comparable except that individuals in the post-implementation group were older, on average, and that a smaller proportion of them were already enrolled in HIV care before being diagnosed with tuberculosis (Table 1).

Delay to initiation of antiretroviral therapy

Among patients initiating ART, the median time to ART initiation after the diagnosis of tuberculosis declined from over 6 weeks before implementation to just over 3 weeks after implementation (Table 2). Significant decreases in time to ART initiation were seen in analysis of subgroups based on baseline CD4+ cell count, type of tuberculosis, sex and point of entry into care. Pre-implementation, 23% and 65% of individuals initiating ART did so by the end of week 4 and the end of week 8 after being diagnosed with tuberculosis, respectively (Fig. 3). These proportions increased to 62% and 90% after implementation. The post-implementation period was marked by a progressive and sustained decline in delay to ART initiation (Fig. 2).

Fig. 3. Time to initiation of antiretroviral therapy (ART) after diagnosis of tuberculosis, pre- and post-implementation of the 2010 WHO guidelines, Cambodia, December 2008 to November 2011
Fig. 3. Time to initiation of antiretroviral therapy (ART) after diagnosis of tuberculosis, pre- and post-implementation of the 2010 WHO guidelines, Cambodia, December 2008 to November 2011
TB, tuberculosis; WHO, World Health Organization.Kaplan–Meier graph with data stratified according to CD4+ cell count at time of tuberculosis diagnosis.

Probability of initiating antiretroviral therapy

We calculated the overall probability of starting ART by a certain week for all individuals diagnosed with tuberculosis and we treated pre-ART death as a competing risk (Table 3). The estimated probability of starting ART by weeks 2, 4 and 8 after the diagnosis of tuberculosis increased respectively from 0.8%, 19.5% and 58.0% before implementation, to 3.9%, 51.8% and 78.8% after implementation. The probability of initiating ART by week 8 after the diagnosis of tuberculosis, on the assumption that individuals lost to follow-up had died, was 51.1% and 72.1% pre- and post-implementation, respectively.

Competing risk regression modelling

Both in unadjusted and adjusted analyses, the implementation effect was restricted to the 2- to 6-week period after the diagnosis of tuberculosis, with an adjusted sHR of 2.60 (95% CI: 1.87–3.62). We found an adjusted sHR of 2.44 when pre-ART loss to follow-up was considered on the assumption that individuals lost to follow up had died (Table 4). In addition, a CD4+ cell count of ≤ 50 cells/µL and enrolment in HIV care before the diagnosis of tuberculosis were independently associated with an increased probability of ART initiation by a given week after diagnosis. The delay before ART initiation was longer among cases of smear-negative pulmonary tuberculosis than among cases of extrapulmonary tuberculosis.

Secondary outcomes

Six months after the diagnosis of tuberculosis, the proportion of patients who had died or were lost to follow-up before and after implementation of revised WHO guidelines were 24.0% and 24.2%, respectively (Fig. 4). The proportion retained and on ART increased from 68% pre-implementation to 73% after implementation (adjusted OR: 1.37; 95% CI: 0.85–2.19; P: 0.197). The incidence of toxicity-driven antiretroviral substitution by the end of the sixth month after ART initiation was 10.3% (27/262) during the pre-implementation period and 11.0% (21/190) in the post-implementation period (adjusted OR: 1.18; 95% CI: 0.55–2.18, P-value 0.796). The most common adverse reactions were hepatitis (17 reports), central nervous system toxicity (15 reports) and skin rash (10 reports).

Fig. 4. Patient flowchart and outcomes for tuberculosis patients on antiretroviral therapy (ART), 6 months (6M) after the diagnosis of tuberculosis, Cambodia, December 2008 to November 2011
Fig. 4. Patient flowchart and outcomes for tuberculosis patients on antiretroviral therapy (ART), 6 months (6M) after the diagnosis of tuberculosis, Cambodia, December 2008 to November 2011
HIV, human immunodeficiency virus; LTFU, lost to follow-up; TB, tuberculosis.Note: The values in the figure represent absolute patient numbers followed by percentages within parentheses. Adult ART-naïve patients with tuberculosis and co-infection with HIV were recruited in the 18 months before and after the implementation of the 2010 World Health Organization guidelines on ART initiation. “Lost to care” refers to patients that either died or were defined as LTFU.

Discussion

Clinical trials are pivotal in identifying novel therapeutic approaches. However, the impact of any approach depends on its effective implementation in routine clinical services. We assessed the impact of the revised WHO guidelines on ART initiation after a diagnosis of tuberculosis in patients with HIV infection attending an urban nongovernmental hospital. After implementation of the new guidelines, ART delays were substantially shortened and initiation of ART occurred earlier on average. Non-significant increases in retention on ART and in ART toxicity were also noted. Our findings support the safety and feasibility of initiating ART early in real-life settings, even in a patient population with advanced HIV infection. To the best of our knowledge, this study is among the first formal and explicit evaluations of these guidelines in such settings.

The before–after study design has limitations; factors not accounted for in the model could have contributed to shortening the time to ART initiation. Following WHO and national guidelines, beginning in March 2011 our programme changed its tuberculosis screening criteria for HIV-positive patients and implemented isoniazid preventive therapy.46 Concurrent with the national scaling-up of ART services, a gradual reduction in enrolment of HIV patients was seen from early 2009 on, and proportionally fewer cases of tuberculosis were diagnosed within the HIV care programme after implementation of the revised WHO guideline. The overall reduced burden of co-infection with HIV and tuberculosis and/or the detection of tuberculosis at a less advanced stage after revised guideline implementation could have made it easier to initiate ART earlier. However, no waiting lists for ART were observed during the study period. Furthermore, the overall burden of work in the clinics remained constant throughout, and patient characteristics were fairly similar before and after implementation. It is possible that dissemination of the WHO rapid advice (November 2009) before the publication of the 2010 WHO guidelines sensitized HIV and tuberculosis care physicians and resulted in their initiating ART earlier before the guidelines were officially implemented. Although all these factors may have been influential, the rapid and sustained reduction in the time to ART initiation following implementation of the revised WHO guidelines suggests that this was the main factor contributing to the reduction.

An increasing number of studies from routine services in resource-limited settings have reported increased and expedited ART uptake,2635 especially after the introduction of a package of interventions aiming at achieving integration of tuberculosis and HIV care. These studies generally precede the 2010 WHO ART guidelines. Median ART delays of 7 and 11 weeks in Uganda and South Africa, respectively, were still observed after integration in recent studies.29,32 An interesting aspect of our study is that early ART initiation was implemented as a single intervention, without major concurrent changes in the tuberculosis/HIV service delivery model. This makes it possible to better quantify the effect of the revised guidelines and to demonstrate their impact when coordination of tuberculosis/HIV activities is fairly well organized. In this regard, the increase we observed in ART initiation by week 4, from 23% to 62% after the 2010 WHO guidelines were implemented, is encouraging. As expected, the time between the diagnosis of tuberculosis and ART initiation was shorter for individuals who had enrolled in HIV care before being diagnosed with tuberculosis. Increased HIV testing and enrolment in HIV care would also provide opportunities for enhanced tuberculosis case-finding and prevention through timely ART initiation. Since reducing the burden of tuberculosis and HIV co-infection will require a range of collaborative activities involving tuberculosis and HIV services, WHO has recently re-emphasized the need to provide quality-assured, integrated preventive, diagnostic and treatment services for both tuberculosis and HIV infection.47

Several questions remain to be explored. Although improved patient outcomes have been reported with increased and expedited ART uptake,47 the survival benefit of initiating ART early (within 2–4 weeks of tuberculosis treatment) for individuals with advanced HIV infection has not been demonstrated yet in routine practice. We observed a non-significant increase in patient retention, but since death ascertainment among losses to follow-up improved over time owing to active tracing of patients by telephone, meaningful comparison of mortality could not be made. Future studies should aim for longer patient follow-up and larger samples to assess the impact on overall patient outcomes. Additional relevant information would include data on the immune reconstitution inflammatory syndrome, drug toxicity associated with antituberculosis agents, and treatment adherence. We note that ART toxicity occurred frequently over the entire study period. Of interest, two recent, relatively small clinical trials in Ethiopia and Thailand did not show a survival benefit with earlier ART initiation.48,49 How the clinical benefit of initiating ART earlier varies across patient populations and programme settings remains to be defined.

After the implementation of the revised WHO guidelines, around 30% of the individuals with advanced HIV infection still initiated ART more than 4 weeks after being diagnosed with tuberculosis. Moreover, many others were lost to care soon after the diagnosis and before initiating ART, and the same has been noted in other programmes.6,20,24 Additional operational research focusing on the underlying causes of ART delay in such patients could reveal the programmatic adjustments needed to achieve higher rates of early ART initiation. More information on outcomes, reasons for early losses to care and possible barriers to ART would be valuable as well.23,50

This study has several limitations. They include the retrospective design, the use of programme data, and the possibility of residual confounding. Tuberculosis might have been missed or falsely diagnosed in some patients. However, the study, which reflects routine service delivery in resource-limited settings, served the purpose of assessing operational feasibility and changes in ART delay in the period after the implementation of WHO’s revised guidelines. Moreover, it revealed a higher proportion of cases of extrapulmonary tuberculosis than other studies. The latest WHO recommendations have been slightly modified and now allow for ART delays beyond 2 weeks in patients with less advanced HIV infection.47 The study was restricted to a single, well-staffed and well-functioning urban hospital where HIV and tuberculosis care services were hosted on the same premises. Consequently, our findings might not apply to settings with less coordination of tuberculosis and HIV care activities. Additional data on operational feasibility from a wide range of clinical settings would be valuable, especially in a context of referrals between ART and tuberculosis clinics widely separated from each other geographically or in settings with poor integration of tuberculosis and HIV care services.5,18,47

Conclusion

The implementation of the 2010 WHO guidelines on ART initiation in patients with tuberculosis was associated with a substantial shortening of the time from tuberculosis diagnosis to ART initiation and with an increased probability of ART initiation by week 8 after the tuberculosis diagnosis. Additional factors associated with a shorter time to ART initiation included a baseline CD4+ cell count of ≤ 50 cells/µL and enrolment in HIV care before being diagnosed with tuberculosis. Although these findings support the operational feasibility of implementing the revised guidelines in routine clinical services, larger studies in different settings and with long-term outcome data are warranted.


Funding:

The HIV programme was supported by the Belgian Directorate General of Development Cooperation through the framework agreement with the Institute of Tropical Medicine, Antwerp, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and HOPE worldwide. JvG is supported by the InBev-Baillet Latour Fund. NL is supported by a grant from the Research Foundation-Flanders.

Competing interests:

None declared.

References

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