HIV indicates human immunodeficiency virus; IPT, isoniazid preventive
therapy; TB, tuberculosis.
Grant AD, Charalambous S, Fielding KL, Day JH, Corbett EL, Chaisson RE, De Cock KM, Hayes RJ, Churchyard GJ. Effect of Routine Isoniazid Preventive Therapy on Tuberculosis Incidence Among HIV-Infected Men in South AfricaA Novel Randomized Incremental Recruitment Study. JAMA. 2005;293(22):2719-2725. doi:10.1001/jama.293.22.2719
Author Affiliations: London School of Hygiene
and Tropical Medicine, London, England (Drs Grant, Fielding, Day, Corbett,
De Cock, Hayes, and Churchyard); Aurum Health Research, Johannesburg, South
Africa (Drs Charalambous, Day, and Churchyard); and Johns Hopkins University,
Baltimore, Md (Dr Chaisson).
Context Tuberculosis preventive therapy reduces tuberculosis incidence among
human immunodeficiency virus (HIV)–infected individuals in clinical
trials, but implementation has been limited and there are no data on effectiveness
under routine conditions.
Objective To determine the effect on tuberculosis incidence of a clinic providing
isoniazid preventive therapy to HIV-infected adults under routine conditions.
Design, Setting, and Participants Randomized intervention study with a novel incremental recruitment design.
Between 1999 and 2001 (before antiretroviral therapy was available), 1655
HIV-infected male employees of a South African gold-mining company (median
age, 37 years) were enrolled in the study. Median follow-up was 22.1 months.
Intervention Employees were invited in random sequence to attend a workplace HIV
clinic. Isoniazid, 300 mg/d, was self-administered for 6 months among attendees
with no evidence of active tuberculosis.
Main Outcome Measure Incidence of tuberculosis (including both first and recurrent episodes)
during the periods before and after clinic enrollment.
Results A total of 1016 of 1655 men included in the analysis attended the clinic
at least once. Six hundred seventy-nine (97%) of 702 men eligible to start
primary isoniazid preventive therapy did so. The tuberculosis incidence rate
before vs after clinic enrollment was 11.9 vs 9.0 per 100 person-years, respectively
(incidence rate ratio [IRR] after adjustment for calendar period, 0.68; 95%
confidence interval [CI], 0.48-0.96). In a multivariable analysis adjusting
for calendar period, age, and silicosis grade, the tuberculosis IRR for clinic
enrollment was 0.62 (95% CI, 0.43-0.89). In a further analysis excluding individuals
with a history of tuberculosis (and, hence, ineligible for isoniazid preventive
therapy), the adjusted IRR for clinic enrollment was 0.54 (95% CI, 0.35-0.83).
Conclusions Enrollment in a clinic offering primary isoniazid preventive therapy
to HIV-infected adults reduced tuberculosis incidence by 38% overall and by
46% among individuals with no history of tuberculosis prior to the study.
Tuberculosis incidence remained high despite isoniazid preventive therapy,
and further work is needed to determine how to use additional interventions
most effectively to reduce morbidity and mortality due to tuberculosis in
A major consequence of the human immunodeficiency virus (HIV) epidemic
in developing countries is the increasing incidence of tuberculosis (TB).1- 3 The cornerstone of TB
control programs is the World Health Organization (WHO) strategy known as
DOTS (directly observed therapy, short course), which may be effective in
controlling drug resistance but appears insufficient to stem rising TB incidence
in regions with high HIV prevalence.4,5
The impact of HIV on TB is illustrated by data from gold mines in South
Africa, where overall TB incidence now exceeds 4000 per 100 000 population
per year (ie, 4%).6 Tuberculosis incidence
was already high in this setting before the spread of HIV infection, largely
because of a high prevalence of silica dust exposure.7 Rising
HIV prevalence has resulted in increasing TB incidence,8 despite
well-implemented TB control programs using directly observed rifampicin-based
short-course chemotherapy and active case detection using an annual miniature
chest radiograph screening program. Additional interventions are required
to reverse the rise of TB in such settings.5
Clinical trials have shown that primary TB preventive therapy (ie, treatment
to prevent a first episode of TB among those with no history of the disease)
reduces TB incidence among HIV-infected individuals. Results of a meta-analysis
suggest that isoniazid preventive therapy (IPT) reduces TB incidence by 42%
overall, or by 60% among individuals who have positive tuberculin skin tests.9 Isoniazid preventive therapy is recommended by WHO
and the Joint United Nations Programme on HIV/AIDS (UNAIDS),10 but
this recommendation has not been widely implemented, partly because of operational
obstacles. These include attrition during assessment for IPT, particularly
nonreturn for tuberculin skin test results and noncompletion of a screen for
active TB if it requires travel to another site to undergo chest radiography.11,12
In collaboration with the mining health service, we established a clinic
for HIV-infected employees in a gold mining company in South Africa in 1999.13 The aim of the clinic was to provide specialist care
for HIV-infected employees, including preventive therapy (isoniazid and cotrimoxazole)
against opportunistic infections. Using a randomized incremental recruitment
study design, we took the opportunity of implementation of this service to
evaluate the effect of these interventions when used as part of routine clinical
care. In this article we describe the effectiveness of IPT.
This was an intervention study with randomized incremental recruitment,
designed to examine the effect of clinic enrollment on episodes of severe
HIV-related disease. This study design has the advantage of not requiring
an untreated control group because all participants have the opportunity to
receive the intervention; it also allows the effect of disease progression
over calendar time among individual participants to be taken into account
in the analysis, as described below. It has been used in community randomized
trials14 but, to our knowledge, has not previously
been used to randomize the order of individuals to be offered an intervention.
The study population consisted of employees of the gold-mining company
who had previously tested positive for HIV within the company health service.
In July 1999, we used computer-generated random numbers to arrange these employees
in a random sequence and invited them to enroll at the clinic in this sequence.
Each employee was interviewed individually and confidentially by a member
of the research staff, who explained the aims of the clinic and invited him
to attend. Those who agreed were given a clinic appointment, and written (or
for participants who could not read, witnessed oral) informed consent was
obtained. Those who declined were given contact details so that they could
make an appointment later if they wished. Employees who missed their first
clinic appointment were offered 2 further appointments. Health care staff
could refer HIV-infected individuals to clinic at any time if clinically indicated.
The study was approved by the research ethics committees of Anglogold
Health Service, Orkney, South Africa, and the London School of Hygiene and
Tropical Medicine, London, England.
Clinic procedures are described elsewhere.13 At
the first visit, trained nurses or research assistants took a medical history
based on information from the patients as well as information in their company
medical records, which document all contacts with the mining health services
since the start of employment. The history focused on HIV-related symptoms,
particularly those suggesting TB, and any history of HIV-related disease.
A physician reviewed the history and performed a physical examination. All
patients were routinely screened for active TB at clinic entry using reported
symptoms, a chest radiograph, and 2 sputum specimens examined by smear and
culture for mycobacteria.
Isoniazid, 300 mg/d, self-administered for 6 months or for 12 months
if there was coincident silicosis, was offered routinely at clinic enrollment
to attendees with no evidence of active TB; in accordance with current WHO/UNAIDS
guidelines, IPT was not offered to individuals with a history of previous
treatment for TB. Tuberculin skin tests were not routinely performed because
the majority of employees were assumed to have latent TB infection.15 Cotrimoxazole, 960 mg/d, was offered to individuals
with a CD4 cell count below 200 × 106/L or below 250 ×
106/L if they had symptomatic HIV disease. Individuals receiving
isoniazid or cotrimoxazole collected their medication from their primary health
center each month, at which time they were asked about symptoms suggestive
of adverse events or of active TB. If these symptoms were present, they were
referred to the clinic for further evaluation. Neither antiretroviral therapy
(ART) nor viral load quantification was routinely available during the period
of this study but are now freely available to employees of this company who
fulfill appropriate medical criteria.
Clinic attendees were seen routinely every 6 months, or sooner if they
were unwell. At each visit, information about episodes of illness in the previous
6 months was recorded. In addition, all hospital admissions of study participants
were identified by research staff using the health service information systems.
Research staff visited patients on the wards and, after discharge, a diagnosis
was assigned using predetermined case definitions. All episodes of TB were
recorded in a dedicated health service database, which was reviewed to ensure
that all episodes of TB among participants were identified. As a further check,
we reviewed the medical records of all participants at the time of study end
or loss to follow-up to ensure that all TB episodes were identified. Employment
records were used to identify dates of loss to follow-up because of termination
of employment or death.
Health service policy at the time of this study entailed suspected TB
to be investigated with a chest radiograph and 3 sputum samples sent for microscopy
and mycobacterial culture. Medical records were used to determine the clinical
disease stage of each individual at the start of the study (July 1999) using
the WHO staging system.16
Individuals were classified as having pulmonary TB if they had compatible
clinical or radiological features and (1) were sputum culture–positive
for Mycobacterium tuberculosis with more than 5 colonies
(categorized as definite); (2) were sputum smear–positive for acid-fast
bacilli or had new radiological changes suggestive of TB but no response to
5 days of antibiotic treatment and improved after 2 months of TB treatment
(categorized as probable); or (3) had no other cause of disease found and
improved after 2 months of TB treatment or were lost to follow-up before 2
months (categorized as possible). Individuals were classified as having extrapulmonary
TB if they had compatible clinical features and either (1) had M tuberculosis isolated from a relevant site (categorized as definite);
(2) improved after 2 months of TB treatment and had other diagnostic evidence
(eg, acid-fast bacilli, caseation, granuloma, characteristic cerebrospinal
fluid or radiological features) (categorized as probable); or (3) had no other
cause of disease found and improved after 2 months of TB treatment or were
lost to follow-up before 2 months (categorized as possible).
Recurrent episodes of TB were included in the analysis only if the outcome
of the previous TB episode was cure or treatment completion.
All mine employees have an annual fitness examination that includes
screening for TB using a miniature chest radiograph. We located the latest
available miniature chest radiograph for all participants taken prior to July
1, 1999, and a single reader assessed the presence and grade of silicosis
using a modified International Labour Organisation grading system.17 Grades 0/1, 1/0, and 1/1 were regarded as possible,
probable, and early silicosis, respectively, and all higher grades were regarded
as advanced silicosis.
Concentrated sputum specimens were stained with auramine and examined
using fluorochrome microscopy. Sputum was cultured for mycobacteria on Lowenstein-Jensen
medium; cultures with more than 5 colonies underwent colorimetric ribosomal
RNA hybridization testing for M tuberculosis (Accuprobe M tuberculosis complex probe kit, Gen-Probe Inc, San Diego,
Calif) to distinguish them from nontuberculous mycobacteria.
Data were analyzed using STATA software, version 7 (Stata Corp, College
Station, Tex). Individuals contributed follow-up time to the “preclinic”
phase from July 1, 1999, until the actual date of their first clinic visit,
and to the “postclinic” phase thereafter. Follow-up ended when
an individual left employment or at the end of the study period (September
30, 2001), whichever was sooner. A Poisson random-effects model was used to
compare the incidence of TB in the phases before and after recruitment to
the clinic. We allowed for multiple TB events rather than censoring after
the first event because otherwise individuals with more advanced HIV disease,
who would be more likely to acquire TB early in the study, would have been
excluded from the postclinic phase, resulting in a “healthy survivor”
We used a random-effects model to allow for the lack of statistical
independence resulting from observation of multiple events in some individuals
and correlation between events in the same individual in different time periods.18 Results were adjusted for the potential confounding
effect of calendar period to take account of HIV disease progression, leading
to increasing TB incidence among all individuals over time. Results were also
adjusted for baseline age, WHO HIV disease stage, and silicosis grade. We
excluded from the analysis all person-time during TB treatment. Since all
patients were screened for TB at clinic entry, we excluded all TB episodes
diagnosed within 90 days of clinic entry on the assumption that these were
diagnosed as a result of this screening process. To avoid bias, for all individuals,
the 90 days following clinic entry were also excluded from the total person-time
In July 1999, 2135 individuals were identified who had had a positive
HIV test result within the mining health service and were still in employment,
and they were allocated a random sequence for recruitment. The first individuals
were seen in clinic later the same month. The last individuals to be recruited
were enrolled in clinic in September 2001, and follow-up ended on September
Of these 2135 individuals, 237 were excluded because we could not obtain
their full medical records, 172 were excluded because they received isoniazid
prior to study entry as part of a separate clinical trial, 30 declined to
participate, 27 were receiving TB treatment at the start of the study and
were lost to follow-up before completing treatment, and 12 had left employment
before the study start date (Figure).
Because the number of women available for inclusion in the analysis was so
small (n = 2), we also excluded them, leaving 1655 men in this analysis.
Among the 1655 men in this analysis, the median age was 37 years (interquartile
range [IQR], 33-43 years), and among the 1650 with WHO HIV disease stage16 recorded at the start of the study, 1176 (71%) were
in stage 1, 109 (7%) were in stage 2, 267 (16%) were in stage 3, and 98 (6%)
were in stage 4.
One thousand sixteen individuals (61%) attended clinic at least once
during the study period. Of these, 950 (94%) were referred to clinic by the
study team on the basis of the randomized sequence and 66 (6%) were referred
by health service staff earlier than the date assigned by the randomization.
Among 639 individuals who did not attend clinic during the study period,
the reasons were termination of employment for nonmedical reasons prior to
clinic enrollment (n = 423 [66%]); death (n = 97 [15%]);
study termination before first clinic attendance (n = 95 [15%]);
termination of employment for medical reasons (n = 18 [3%]); and
other (n = 6 [1%]) (Figure).
Six hundred seventy-nine individuals (67%) who first attended clinic
during the study period started isoniazid. The main reasons for not starting
isoniazid were contraindication (270/337 [80%]), most commonly history of
TB (240/270 [89%]), or suspected active TB (26/337 [8%]). The median CD4 cell
count among individuals who started isoniazid was 371 × 106/L
(IQR, 252-530 × 106/L; data from 619/679 participants) compared
with 277.5 × 106/L (IQR, 171-444 × 106/L;
data from 210/240 participants) among individuals who did not start isoniazid
because they had a history of previous TB (P<.001
by Mann-Whitney U test).
The median duration of follow-up was 22.1 months (IQR, 13.7-27.0 months)
overall; the median duration of follow-up before clinic enrollment was 11.2
months (IQR, 6.6-18.5 months) and after clinic enrollment (among individuals
who ever attended clinic) was 11.0 months (IQR, 5.7-17.9 months).
In total, there were 254 TB episodes meeting study case definitions;
225 individuals had 1 episode, 13 had 2 episodes, and 1 had 3 episodes of
TB. Of these episodes, 189 (74%) were classified as definite, 52 (20%) as
probable, and 12 (5%) as possible cases; 1 was unknown. One hundred seventy-three
episodes (68%) were of pulmonary TB only, 46 (18%) were extrapulmonary TB
only, and 35 (14%) were both pulmonary and extrapulmonary. The most common
sites for extrapulmonary TB were pleural space (30 cases) and lymph nodes
(19 cases). Thirty-nine TB events that occurred within 90 days of clinic entry
were assumed to have been diagnosed as a result of active screening at clinic
entry and were excluded from the analysis, along with 219.1 person-years of
follow-up during these 90 days.
The overall incidence of TB was 11 per 100 person-years; prior to clinic
enrollment, TB incidence was 11.9 per 100 person-years compared with 9.0 per
100 person-years following clinic enrollment (incidence rate ratio [IRR],
0.78; 95% CI, 0.58-1.05; P = .10). After
adjustment for the confounding effect of calendar period, the IRR for the
effect of clinic enrollment on TB incidence was 0.68 (95% CI, 0.48-0.96; P = .03).
Table 1 shows a univariable analysis
of risk factors for incidence of TB and analysis of the same risk factors
after adjustment for the potential confounding effect of calendar period,
categorized into 6-month time bands. The risk of TB was significantly associated
with increasing age, history of TB, baseline WHO HIV disease stage 3 or 4
(compared with stage 1 or 2), and a silicosis grade of “probable”
or higher. Adjustment for calendar period did not substantially alter these
In a multivariable analysis (Table 2)
examining the effect of clinic enrollment on the incidence of TB, adjustment
for age, previous TB, and baseline WHO HIV disease stage did not substantially
affect the result, but adjustment for baseline silicosis grade (based on 1367
individuals with an available silicosis grade) strengthened the effect, giving
an adjusted IRR of 0.62 (95% CI, 0.43-0.89; P = .009).
Restricting the analysis to cases of TB classified as definite did not change
these results, nor did analyses increasing the period of time after clinic
entry (up to 180 days) during which TB cases were excluded, assuming they
had been detected by screening at clinic entry (data not shown). Analyses
controlling for calendar period using narrower time bands did not affect the
In a further analysis excluding individuals who had a history of TB
at the time of randomization and were therefore ineligible for IPT from the
beginning of the study (Table 2), the
IRR, adjusted for calendar period among the remaining 1310 individuals, was
0.62 (95% CI, 0.41-0.93; P = .02). Further
adjustment for age and silicosis grade (based on 1041 individuals with an
available baseline silicosis grade) gave an adjusted IRR of 0.54 (95% CI,
0.35-0.83; P = .004).
Nine patients discontinued isoniazid because of a possible adverse event.
Eight of these were because of skin hypersensitivity; 1 also had mild hepatitis.
Two of these 8 individuals subsequently restarted isoniazid. The ninth discontinued
because of mild peripheral neuropathy. An additional 13 individuals were reported
to have peripheral neuropathy and 9 to have skin hypersensitivity, but all
completed the course of isoniazid.
We used a novel study design to investigate the effect on TB incidence
of a clinic providing IPT to HIV-infected adults under routine conditions.
A reduction in TB incidence of 38% overall may appear modest in comparison
with clinical trials, and some important differences in study design must
be considered. First, adherence to treatment may have been less than that
in clinical trial conditions, which may have resulted in a reduced effect.
Second, IPT was not restricted to individuals who had a positive tuberculin
skin test result, among whom the protective effect is consistently stronger.9,19 Since it is assumed that the majority
of men in this population have latent TB infection, this is unlikely to have
affected the results substantially. Third and most important, the overall
analysis tests the effect of the intervention (the provision of clinic services)
among the entire study population, irrespective of whether they actually received
isoniazid. Overall, about one third of clinic attendees did not receive isoniazid,
most often because they had previously had TB, making them ineligible according
to current guidelines. When restricting the analysis to individuals who had
no history of TB at the start of the study, clinic enrollment resulted in
a 46% reduction in TB incidence. However, this analysis still includes individuals
who had TB during the preclinic phase, who would subsequently have been at
higher risk of TB but did not receive IPT because they were ineligible by
the time they were enrolled in clinic. Hence, this is probably an underestimate
of the protective effect of IPT among individuals with no history of TB.
Two further points are relevant to the interpretation of the results:
the study was carried out over a relatively short period because, for ethical
reasons, we needed to recruit eligible individuals to clinic as quickly as
logistically possible. Thus, our follow-up period after clinic entry was relatively
short, and follow-up time after completion of the 6-month course of isoniazid
was even shorter. Evidence suggests that the protective efficacy of TB preventive
therapy, particularly non–rifampicin-containing regimens, wanes over
time.20,21 Thus, our estimate
of protective efficacy may have been higher than would be observed over longer
follow-up. Finally, screening for TB at clinic entry and exclusion of any
cases of TB detected at this point will have reduced the incidence of TB in
the postclinic phase. Including these cases detected at clinic entry in the
calculation of postclinic TB incidence would have created bias, since there
was no equivalent active case finding at the start of the preclinic phase
and, hence, we excluded these cases.
The effect of screening for TB on TB incidence in the postclinic phase
will have been short-lived: in another study in this setting, TB incidence
was reduced after active screening for TB, but 180 days after screening, TB
incidence had returned to prescreening rates.22 In
addition, an episode of active TB detected at clinic entry must have had its
onset in the preclinic phase and so arguably belongs more correctly in the
preclinic phase. Subsequent clinic visits and, perhaps, more thorough investigation
of TB symptoms among individuals attending clinic may have increased the probability
of detecting a TB episode in the postclinic phase. Since routine clinic visits
were at 6-month intervals and other work by this group has found that the
duration of TB disease before diagnosis is reduced in HIV-infected compared
with uninfected individuals,23 this effect
is unlikely to have been large. If TB cases were more likely to be detected
in the postclinic phase, this would result in underestimation of the effectiveness
of the clinic to reduce TB incidence.
Despite our intervention, the TB incidence rate in the postclinic phase
remained unacceptably high at 9 per 100 person-years. This may be partly due
to the prevalence of silicosis, but additional strategies are clearly required
to further reduce TB incidence in this population. In this study, a history
of TB was a risk factor for a subsequent episode. Individuals with a history
of TB had lower median CD4 cell counts at clinic entry than those with no
history of TB, putting them at higher risk of TB.24- 26 Although
current guidelines do not recommend secondary TB preventive therapy (ie, for
individuals with a previous history of TB), there is an increasing body of
evidence to support its effectiveness.26 In
settings of high TB prevalence, it seems illogical to withhold TB preventive
therapy from individuals with a history of TB, especially those with low CD4
cell counts, whose risk of TB is highest. Further work is needed to determine
the optimum duration of TB preventive therapy.
ART is now being rolled out among the mining workforce. ART has been
shown to reduce TB incidence at the individual level,25,27 although
in a setting with high TB prevalence, TB incidence remained high even among
individuals receiving ART.25 However, there
are concerns that ART could paradoxically increase TB incidence at the community
level if the net effect is to increase survival among HIV-infected individuals
without completely restoring immunocompetence.28,29 Further
work is required to determine if these concerns are borne out in practice
and to establish how best to use ART and TB preventive therapy to minimize
morbidity and mortality due to TB among HIV-infected individuals.
In settings where TB prevalence and, hence, risk of transmission are
very high, more radical approaches to TB control may be necessary, such as
communitywide screening and preventive therapy for all found not to have active
disease.30 Such approaches may have only short-term
benefit if the underlying risk factors are not altered, and will require careful
Concerns are often raised about the risk of promoting isoniazid resistance
when isoniazid is used as a single agent in preventive therapy. Studies from
the pre-HIV era did not support this concern,31 but
close monitoring of resistance patterns to TB drugs is very important. We
have too few data from this study on drug resistance among individuals who
previously received IPT to report meaningful trends, but surveillance continues.
Another concern is the risk of isoniazid-induced hepatitis; our study is reassuring
in that only 1 individual was noted to have mild hepatitis during the study.
In conclusion, we found that enrollment in a clinic for HIV-infected
individuals routinely providing IPT reduced the incidence of TB by 38% overall
and by 46% among individuals with no history of TB, after adjustment for confounding
factors. Additional interventions such as secondary preventive therapy and
ART will be required to reduce the very high residual morbidity attributable
to TB in this community. Further work is needed to determine how best to use
available interventions to minimize TB morbidity in areas where both HIV and
TB are highly prevalent.
Corresponding Author: Alison D. Grant, MBBS,
PhD, Clinical Research Unit, Department of Infectious and Tropical Diseases,
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E
7HT, England (email@example.com).
Author Contributions: Dr Grant had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Grant, Corbett, Chaisson,
De Cock, Hayes, Churchyard.
Acquisition of data: Grant, Charalambous, Day,
Analysis and interpretation of data: Grant,
Fielding, De Cock, Hayes, Churchyard.
Drafting of the manuscript: Grant, Churchyard.
Critical revision of the manuscript for important
intellectual content: Grant, Charalambous, Fielding, Day, Corbett,
Chaisson, De Cock, Hayes, Churchyard.
Statistical analysis: Grant, Fielding, Hayes.
Obtained funding: Grant, Churchyard.
Administrative, technical, or material support:
Grant, Charalambous, Day, Corbett, Chaisson, Churchyard.
Study supervision: Grant, Hayes.
Financial Disclosures: None reported.
Funding/Support: This study was funded by Anglogold
PTY (Ltd). Dr Grant is supported by a UK Department of Health Public Health
Career Scientist award. Dr Corbett is supported by a Wellcome Trust Career
Development Fellowship. Dr Chaisson is supported by National Institutes of
Health grant AI01637.
Role of the Sponsor: The funding organization,
Anglogold PTY (Ltd), had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; or preparation, review,
and approval of the manuscript. The funding organization gave permission for
the results to be published at the time the study was commissioned. Anglogold
Health Services PTY (Ltd) participated in the development and implementation
of the clinic and is a subsidiary of Anglogold. At the time of the study,
Aurum Health Research was an independent subsidiary of Anglogold Health Services.
Acknowledgment: We thank the participants;
the staff of Ernest Oppenheimer Hospital, Welkom, South Africa, particularly
those from the TB laboratory, the radiology department, the TB clinic, and
the prevention clinic; and the staff of Aurum Health Research, particularly
Evanne Rothwell, Clement Sefuthi, Themba Moyake, and Edwin Magcuntsu, for
their essential contributions to data collection.