The global tuberculosis (TB) and HIV epidemics in sub-Saharan Africa are closely intertwined. South Africa has the greatest number of HIV-infected individuals and among the highest TB incidence rates worldwide.1-3 More than 65% of all active TB patients are coinfected with HIV, and TB is the leading cause of morbidity and mortality among HIV-infected patients.4 Despite the widespread availability of TB treatment, TB/HIV-coinfected patients had an annual mortality rate of 25%-40% before the introduction of antiretroviral (ARV) therapy.4,5 This mortality was attributable to both complications from overwhelming TB disease and immunosuppression from advanced HIV disease.6,7 Thus, efforts to reduce mortality in TB/HIV-coinfected patients must focus on both improving TB treatment completion rates and on providing HIV care and ARV therapy.8,9
Many challenges have existed to providing effective treatment for TB/HIV-coinfected patients. Until recently, ARV therapy was not available in most of sub-Saharan Africa, not only due to high costs but also due to a lack of health care infrastructure to safely and effectively utilize such therapy. Although TB treatment programs have long existed throughout South Africa, treatment completion rates remain near 60%, well below the World Health Organization (WHO) 85% standard, primarily due to a 3- to 4-fold increase in TB case load in the past decade. Integration of TB and HIV care is a promising strategy for addressing the need for infrastructure to provide HIV care and the need for additional resources for TB programs.8,10
Although the potential benefit of integration between TB and HIV programs has long been recognized,11,12 few successful examples have been reported to date.13 Concerns over drug-drug interactions, overlapping toxicities, and immune reconstitution inflammatory reactions, in addition to fear of nosocomial transmission of TB, have made physicians reluctant to provide both TB and ARV therapy concurrently.14 Historically separate administration and funding have also separated TB and HIV programs at all levels.15 The resulting scenario is one where TB and HIV care are provided by separate doctors, nurses, and staff, in different clinics or locations, with little or no communication or coordination. Consequently, patients are diagnosed and treated for either HIV or TB, but not both, leaving them vulnerable to complications of the other disease.
In an effort to address these barriers to effective care for TB/HIV-coinfected patients, we devised a TB/HIV integration strategy to provide concomitant TB and ARV therapy by modified, directly observed therapy (DOT).8,16 Key components of this strategy include strengthening and adaptation of a preexisting TB DOT infrastructure, patient adherence education, training of community health workers (DOT supporters) and family members to provide treatment support and adverse reaction monitoring, and a once-daily ARV regimen of efavirenz, lamivudine, and didanosine to enable simultaneous daily administration with the standard TB regimen. In this report, we demonstrate this strategy's feasibility, effectiveness, and safety in a rural, resource-limited setting in South Africa.
The study was conducted in the Msinga, subdistrict of KwaZulu-Natal, South Africa, an impoverished, 2000-km2 rural area, which is home to 200,000 traditional Zulu people. The majority of homes lack electricity or running water, and the unemployment rate is 42%. A 355-bed provincial government district hospital provides health care for this population. Forty percent of the hospital's beds are occupied by HIV-infected patients, and the prevalence of HIV infection among women presenting to the maternity ward is 25%. The incidence of active TB disease is greater than 1000 per 100,000 population, and more than 80% of all active TB cases are HIV coinfected.17
A government-sponsored TB treatment program, employing the WHO Directly Observed Therapy, Short-Course (DOTS) strategy, has been in place since 1993. Patients receive free TB treatment by home-based, modified DOT, administered by volunteer community health workers (DOT supporters). The standard TB regimen is isoniazid (240 mg), rifampicin (480 mg), ethambutol (1100 mg), pyrizinamide (1200 mg), and pyridoxine (25 mg), Monday through Friday for 2 months, followed by 4 months of isoniazid and rifampicin Monday through Friday. TB diagnosis at the time of this study was made by sputum microscopy for acid-fast bacilli, x-ray, or clinical criteria, according to the South African National TB Guidelines.18 Follow-up sputum microscopy is performed at 2 and 6 months. Sputum culture and drug susceptibility testing were not routinely performed for initial TB diagnosis at the time of this study. For patients who were persistently smear positive or clinical treatment failures, mycobacterial culture and drug susceptibility testing was performed. (Detailed methods for culture and susceptibility testing have been previously described.19)
Patients diagnosed with active TB are routinely offered HIV voluntary counseling and testing. Patients found to be HIV infected are referred to a comprehensive HIV program, which has existed at this site since 1998. The HIV program provides cotrimoxazole preventive therapy, management of opportunistic infections, prevention of mother-to-child transmission, and an orphans program. At the time of initiation of this study, ARV medications were not available in the public sector.
Creation of an Integrated TB/HIV Treatment Program
TB Program Strengthening
Additional resources were provided to strengthen the existing TB program, which was struggling to cope with a 3- to 4-fold increase in case load over the previous decade. TB DOT program staff was augmented by 2 program coordinators and 120 additional DOT supporters. A new vehicle was purchased to facilitate coordination between program staff and DOT supporters in the community.
Creation of ARV Program
The ARV program was created by training doctors, nurses, and DOT supporters in the use of ARV medications. An HIV/ARV treatment literacy curriculum was also created for patients, family members, and DOT supporters to attend before starting ARV therapy. A reliable and affordable supply of ARV medications was established through a national wholesale pharmacy and pharmaceutical companies' “direct access” programs. A once-daily ARV regimen of efavirenz (600 mg), lamivudine (300 mg), and didanosine (400 mg) was employed. Laboratory support to provide CD4 cell counts and HIV viral loads was established with a research laboratory at University of KwaZulu-Natal in Durban.
Adherence Program, Treatment Administration, and Clinical Monitoring
Patients were required to complete an HIV/ARV training curriculum, together with a family member of their choice and their DOT supporter, before starting ARV therapy. The curriculum was divided into 4 weekly sessions covering the following topics: natural history of HIV infection, efficacy of ARV therapy, importance of adherence to ARV therapy, and potential adverse events. Upon completion of the curriculum, patients received a 1 month supply of ARV medications at each visit, which they organized onto a “medication calendar,” a paper or cardboard calendar with packets of each day's ARV dose stapled to each day of the month.
Patients' daily TB and ARV doses were observed in their homes by either their DOT supporter or appointed family member. Patients received standard TB therapy Monday to Friday and once-daily ARV therapy 7 days per week. Patients' adherence to treatment was confirmed by regular inspection of the monthly treatment calendar by their DOT supporter and by monthly administration of a standardized 7-day adherence measurement instrument.20 The DOT supporter also assessed patients for any adverse events at each visit to the patient's home. Patients were transitioned to self-administered ARV therapy when they completed their TB treatment course.
Patients were seen in the HIV clinic at the district hospital on a monthly basis for clinical and laboratory assessment. CD4 cell counts and viral loads were measured every 3 months.
Funds for TB strengthening and the creation of the ARV program, including medication and laboratory expenses, were provided by the Irene Diamond Fund, Yale University, and the Continuum of Care Global Fund grant as part of this study protocol.
This is a prospective, operational research study examining the feasibility, effectiveness, and safety of the integrated TB/HIV therapy program described above. Inclusion criteria for the study were as follows: (1) age greater than 18 years, (2) diagnosed active TB,18 (3) documented HIV infection, (4) baseline CD4 cell count less than 350 cells per cubic millimeter, (5) no prior TB treatment default, (6) ARV naive, (7) completion of 1 month of TB therapy by home-based modified DOT, (8) no severe baseline hepatic or renal dysfunction, (9) disclosure of HIV status to a family member who would assist in treatment support, and (10) willingness to take contraception to prevent pregnancy on efavirenz (women of childbearing age).
HIV-infected patients with active TB were referred for study enrollment from either the TB DOT program or the HIV program. Patients were screened for inclusion with a history, physical exam, and baseline laboratory tests. Eligible patients were initiated on ARV therapy upon completion of the HIV/ARV patient literacy curriculum. Patients' daily TB and ARV doses were observed at home by either their DOT supporter or family member as noted above.
After ARV initiation, patients were followed monthly for 1 year. At each visit, patients were administered a standard questionnaire regarding adverse reactions and a 7-day medication adherence recall,20 in addition to having a history and physical exam. A full blood count and chemistries including liver function tests and amylase were measured monthly. CD4 count and viral load were performed every 3 months. Viral resistance testing is not routinely performed; however, plasma samples were stored for future genotyping studies. Patients were reimbursed for transportation expenses incurred to attend clinic visits.
Outcomes and Analysis
The primary outcomes of interest were change in CD4 cell count, viral load, and weight, TB treatment outcome, and survival in the first 12 months after ARV initiation. Secondary outcomes were number and rate of severe adverse events and adherence to ARV medications and clinic visits.
Changes in CD4 cell count and weight and proportion with undetectable viral loads (less than 400 copies/mL) were calculated at 3, 6, 9, and 12 months. TB treatment outcomes were classified as cure, treatment completed, died on therapy, defaulted, or treatment failure, based on WHO TB outcome definitions.21 Adverse events were characterized according to the Division of AIDS, NIH standard protocol using a 5-grade severity measure system.22 Grades 3, 4, and 5 severe adverse events were defined as those requiring hospitalization, life-threatening, or resulted in death, respectively. Rate of severe adverse events was calculated based on the number of severe adverse events and the number of patient-years of follow-up. Adherence to clinic visits was calculated based on the number of visits attended divided by the total number of scheduled visits, adjusting for deaths and withdrawals from study. Adherence to medications was calculated by dividing the number of missed doses reported in the 7 days preceding each study visit by the total number of prescribed doses. Survival was calculated as the number of days survived from the initiation of ARV medications to 1 year. The difference in CD4 count and weight at 6 and 12 months was tested using a paired Student t test. Proportions of viral load suppression and adherence to clinic visits were calculated based on the number of surviving participants at each measurement period. For patients who never suppressed their viral loads, HIV genotyping results were described, if available.
This study was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee, the Yale University Human Investigations Committee, and the Albert Einstein College of Medicine Committee for Clinical Investigation.
A total of 174 TB/HIV-coinfected patients were evaluated for study inclusion, and 119 patients were enrolled from October 2003 to January 2006. Reasons for exclusion are listed in Table 1. Of the 119 enrolled patients, the mean age was 34.0 years (SD = 7.1 years) and there were 67 women (56%) (Table 2). At the initiation of ARV therapy, the mean patient weight was 55.3 kg (SD = 8.0 kg), the median CD4 cell count was 78.5 cells per cubic millimeter [interquartile range (IQR) 42-152 cells/mm3], and the median viral load was 250,000 (5.4 log) copies per milliliter (IQR 120,000-590,000 copies/mL).
Patients initiated ARV therapy a median of 67 days (IQR 60-83 days) after institution of TB therapy. The median increase in CD4 cell count was 151 cells per cubic millimeter (IQR 81-227 cells/mm3, P < 0.001) at 6 months and 211 cells per cubic millimeter (IQR 131-283 cells/mm3, P < 0.001) at 12 months after the initiation of ARV therapy (Fig. 1). Patients' weights increased in parallel by 6.5 kg (SD = 6.5 kg, P < 0.001) at 6 months and 10.5 kg (SD = 7.9 kg, P < 0.001) at 12 months (data not shown). At 6 months, 83% (91/110) of patients had an undetectable viral load (VL < 400 copies/mL), with 88% (92/105) undetectable at 12 months (Fig. 2). The viral loads for 6 (6%) patients were not suppressed at 12 months, of which 5 were found to have viral resistance on genotyping: 4 with efavirenz resistance (K103N, V108M, Y181C, G190S/E), 3 with lamivudine resistance (M184V), and 2 with didanosine resistance (K65R, L74V). The remaining 7 (7%) patients did not have a viral load measured at 12 months because they were lost to follow-up.
A total of 100 (84%) patients were cured or successfully completed their TB therapy (Table 3). The reasons for not achieving cure or treatment completion among the remaining 19 patients were as follows: death while on TB therapy (n = 11, 9%); default (n = 5, 4%); and treatment failure (n = 3, 3%). All 3 patients who remained alive with treatment failure were found to have multidrug-resistant (MDR) (n = 2) or extensively drug-resistant (XDR) TB (n = 1) and were initiated on second-line TB therapy.
Patients attended 1094 (93%) of 1174 study follow-up visits within 1 day of their scheduled visit. Patients reported taking 99% of their ARV doses on the standardized 7-day recall adherence instrument.
A total of 34 severe adverse events were observed during the study period (19.6/100 patient-years). Only 1 severe adverse reaction, pancreatitis (0.6/100 patient-years), was directly related to the study medications or protocol, most likely due to didanosine. Most other severe adverse events were recorded as possibly or probably related to study protocol (eg, nausea, vomiting, anemia) or were unlikely to be related (eg, peptic ulcer, struck by lightening). Sixteen of the 34 severe adverse events (47% or 9.2/100 patient-years) were clinical deterioration or hospitalizations due to MDR TB or XDR TB. No cases of lactic acidosis, hepatitis (clinical or by laboratory monitoring), or peripheral neuropathy, requiring hospitalization or cessation of TB or ARV therapy, were observed. Two (2%) patients experienced immune reconstitution inflammatory syndrome, which required steroid administration but not cessation of ARV therapy (ARVs started 56 and 63 days after TB therapy, respectively).
Thirteen patients (10.9%) died in the 12 months after ARV initiation. Of these, 10 (77%) died of confirmed MDR TB (n = 1), confirmed XDR TB (n = 5), or suspected drug-resistant TB (but died before culture was sent, n = 4); 3 patients died of unknown or other causes (respiratory failure, hematemesis, and acute diarrhea).
The convergence of the TB and HIV epidemics in sub-Saharan Africa has resulted in dramatic increases in morbidity and mortality in the past decade. Despite considerable advocacy for increased collaboration and integration of TB and HIV care,11,23 few models of integration have been implemented, tested, and reported to date.13 In this study, we demonstrate the feasibility, effectiveness, and safety of a strategy of integrating TB and HIV treatment in a rural, resource-limited setting in South Africa; key components of this strategy included using a preexisting TB DOTS infrastructure, once-daily ARV regimen, patient treatment literacy training, and adherence support from trained community health workers and family members. TB/HIV-coinfected patients receiving concurrent ARV and TB therapy by this strategy achieved high levels of adherence and excellent TB and HIV outcomes. Few patients experienced severe adverse events or immune reconstitution reactions. The mortality rate in this study was improved, from the historical 25%-40% annual mortality rate in TB/HIV-coinfected patients before the availability of ARV therapy,4,5 to a rate similar to that published in patients initiating ARVs in other resource-limited settings.24-27 The finding of mortality due to MDR and XDR TB, however, cautions that integration of TB and HIV programs must be implemented carefully and that greater investment in developing and implementing infection control and laboratory infrastructure is needed.
There are several key reasons why our TB/HIV integration strategy was successful. First, we adapted and strengthened a preexisting community-based TB DOTS infrastructure to provide the adherence support and adverse reaction monitoring necessary for success with TB and ARV therapy. This improved infrastructure ensured social support and prompt identification of adverse reactions or other barriers, which may compromise the high adherence level necessary. Secondly, the use of a well-studied, once-daily ARV regimen of efavirenz, lamivudine, and didanosine28,29 was critical to this strategy because it allowed for concurrent administration with the daily TB regimen dose. Additionally, we required all patients participate in an educational curriculum together with their DOT supporter and a family member. The effect of this curriculum was not only to educate and prepare patients for taking TB and ARV therapy but also to empower them, enhance social support, and reinforce a joint responsibility between the patients, family members, and DOT supporters. Finally, reimbursement for travel expenses to clinic visits and study appointments was given to facilitate patients' attendance.
Our strategy also addressed the major concerns related to providing concurrent TB and HIV therapy. We used an efavirenz-based ARV regimen to eliminate concerns of interactions between rifampin and protease inhibitors. Although rifampin has been shown to also diminish levels of efavirenz with concomitant use, its clinical significance is unclear because excellent clinical outcomes have been seen despite wide variability in efavirenz levels.30-32 Immune reconstitution reactions were seen in only 2 patients in this study. Delaying ARV therapy until 6-8 weeks after the start of TB therapy may have diminished the likelihood of immune reconstitution inflammatory syndrome in this study,14,33 although this must be balanced against the concern about early mortality in TB/HIV-coinfected patients. Rigorous randomized trials regarding the optimal timing for ARV therapy are underway, but not yet available.34 Finally, few significant adverse events were seen in our study despite the concerns for overlapping toxicities with concurrent TB and ARV therapy. There was only 1 event (pancreatitis), which was clearly related to the concurrent therapy-most likely, didanosine. No episodes of hepatitis (clinically or by laboratory criteria) or neurologic abnormalities were seen. Even peripheral neuropathy, which is a common reason for switching ARV regimens among patients receiving stavudine in ARV scale-up programs,35-37 was not sufficiently severe in any study patients to necessitate stopping or changing ARV regimens.
Although mortality in this study (11%) was dramatically better than pre-ARV rates for TB/HIV-coinfected patients (25%-40%),4,5 the magnitude exceeded our a priori hypothesis. Cause of death analysis revealed that nearly 80% of deaths in this study were attributable to MDR or XDR TB. This finding spurred a subsequent TB drug-resistance prevalence study, which has been published separately,19 and helped uncover an underlying drug-resistant TB epidemic in South Africa.38 Despite their widespread global prevalence,39 the presence of MDR or XDR TB cases in the context of a TB/HIV integration study raises the issue of whether HIV-coinfected TB patients should receive care in the same settings as other vulnerable HIV patients. Whether transmission of MDR or XDR TB strains occurred among patients in this study is currently unknown; a detailed molecular epidemiology study of our site is underway to answer this question. However, in settings such as ours, where more than 80% of all active TB cases are HIV-coinfected, the greatest risk for TB transmission among HIV patients is an HIV-infected patient with undiagnosed TB. We feel that integrating TB and HIV care improves active case finding and early diagnosis of TB, which in turn, would reduce the risk of TB transmission, not increase it.
Nonetheless, development and implementation of comprehensive infection control programs, based on a 3-level program of controls (administrative, environmental controls, and respiratory protection), must be considered a critical component of any integrated TB/HIV program.23,40,41 Key components of infection control programs in the outpatient setting should include active TB case finding among all HIV-infected patients,11,23 waiting areas which maximize natural ventilation (preferably outdoors),42 and designated “cough monitors,” health care staff who identify coughing patients in waiting areas to rapidly evaluate and isolate them.23 Implementation of currently available, low-cost, infection control measures in hospital settings may also have a dramatic effect in reducing TB transmission in nosocomial settings,42,43 and thus, should also be considered essential in creating a TB/HIV program.
There are several important limitations of our study. We felt it was unethical to randomize patients to not receive ARV therapy, and thus we did not include a control group in our study design. As a result, we do not have a direct comparative group against which to demonstrate the efficacy of our integration strategy. Nonetheless, the mortality among TB/HIV-coinfected patients is generally agreed to be far greater than the 11% found in our study.4,5 Second, although only 1 case of pancreatitis and no cases of lactic acidosis and severe peripheral neuropathy were seen in our study, conclusions based on these findings are limited by our small sample size. Nonetheless, because widespread stavudine use has been accompanied by high rates of lactic acidosis and severe peripheral neuropathy,35-37 consideration should be given to using didanosine in place of stavudine as a first-line agent in South Africa, until other once-daily nucleoside/nucleotide reverse transcriptase inhibitors become widely available (eg, tenofovir). Lastly, since home-based DOT was a critical component to this TB/HIV integration strategy, patients were required to successfully complete 1 month of DOT for TB therapy before they were eligible for this study. This requirement may have selected for less severe illness and thus may have biased our results to a lower mortality and a more adherent study population. Nonetheless, our study adds to the body of literature demonstrating that improvements in CD4 count and viral load, similar to those seen in high-income countries, can be achieved even in remote and resource-limited settings, such as ours in rural South Africa.44,45
In conclusion, our study demonstrates that TB and HIV therapy may be safely and effectively integrated to improve TB and HIV outcomes and mortality in TB/HIV-coinfected patients in resource-limited settings. The integration strategy utilized a once-daily ARV regimen, given concomitantly with standard TB therapy by home-based modified DOT, and resulted in improved clinical outcomes, high levels of adherence, and a low incidence of severe adverse reactions. This strategy can serve as a model for integration of TB/HIV care in other resource-limited settings where TB DOTS programs already exist.
We would like to thank the hospital and clinic staff in Tugela Ferry who have made this study possible and acknowledge their remarkable hard work and dedication. We also acknowledge Dr. Sharon Cassol, who provided laboratory support for this study. We appreciate mentorship support from the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519).
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
tuberculosis; HIV; AIDS; highly-active antiretroviral therapy; South Africa; directly observed therapy