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. Author manuscript; available in PMC: 2012 Aug 15.
Published in final edited form as: Int J Tuberc Lung Dis. 2000 Nov;4(11):1032–1040.

Efficacy of an unsupervised 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis in HIV-infected adults

J L Johnson *, A Okwera †, P Nsubuga †, J G Nakibali †, C C Whalen ‡, D Hom §, M D Cave , Z H Yang , R D Mugerwa **, J J Ellner §, for the Uganda-Case Western Reserve University Research Collaboration
PMCID: PMC3419476  NIHMSID: NIHMS199928  PMID: 11092715

SUMMARY

SETTING

National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda.

OBJECTIVE

To assess the efficacy of a daily, self-administered 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis (TB) in human immunodeficiency virus (HIV) infected adults.

DESIGN

Treatment outcomes in patients with pulmonary TB treated with a single 8-month regimen and followed in a prospective epidemiological study.

RESULTS

Two hundred and sixty-five HIV-infected and 26 non-HIV-infected adults with initial episodes of pulmonary tuberculosis were treated with 2 months of daily isoniazid (INH), rifampicin (RMP), ethambutol and pyrazinamide followed by 6 months of daily INH + RMP. Median follow-up was 17.8 months. Ninety-five per cent of the HIV-infected and all of the non-HIV-infected patients who had sputum examined were sputum culture negative after 2 months of treatment. Twenty-two HIV-infected and no non-HIV-infected patients died during treatment. Relapse rates were 8.4% (5.9 per 100 person-years of observation [PYO], 95%CI 3.2–8.6) among HIV-infected patients and 4.5% (2.1/100 PYO, 95%CI 0–7.8) for non-HIV-infected patients. Adverse drug reactions occurred in 37% of the HIV-infected patients; most were minor and self-limiting.

CONCLUSION

An 8-month RMP-containing regimen was well tolerated and effective in the treatment of HIV-infected adults with initial episodes of pulmonary TB. Relapse rates were similar to those reported with 6-month short-course regimens in HIV-infected individuals. Decisions about the duration of anti-tuberculosis treatment for HIV-infected adults must balance programme resources and the likelihood of poor compliance with longer regimens with the potential for a modest decrease in relapses with longer treatment.

Keywords: tuberculosis, HIV, AIDS, rifampicin, relapse, RFLP

TUBERCULOSIS (TB) is currently the most frequent cause of death in African adults infected with the human immunodeficiency virus (HIV).1 More than 40% of all new tuberculosis cases in many African countries occur among HIV-infected individuals.2–5

HIV infection is associated with progressive immune suppression. Many opportunistic infections in HIV-infected individuals, such as cryptococcal meningitis and Pneumocystis carinii pneumonia, require lengthy treatment and lifelong suppressive or secondary pro-phylactic therapy. These issues have raised concerns concerning the optimal duration and content of regimens for tuberculosis treatment in HIV-infected individuals. Pulido et al. recently reported that treatment of HIV-infected TB patients with less than 9 months of a rifampicin-containing regimen was associated with increased risk for relapse.6 Other studies have documented high success rates comparable to those in non-HIV-infected individuals treated with 6-month short-course regimens.7–9 Current US guidelines recommend therapy for 6 months except in patients with a slow response to treatment,10,11 whereas other nations such as Brazil have routinely treated HIV-infected patients with tuberculosis for 9 months.12 The optimal duration of treatment for HIV-infected individuals with TB is still controversial, and is an important issue for TB control programmes. Longer regimens are more expensive and associated with lower rates of compliance.13

In 1993 the Uganda-Case Western Reserve University Research Collaboration began a prospective cohort study of the effects of tuberculosis on HIV infection. Based on recommendations regarding the duration of anti-tuberculosis treatment in HIV-infected adults at the time the study was initiated, patients were treated with a daily, self-administered, 8-month regimen consisting of 2 months of isoniazid (INH), rifampicin (RMP), ethambutol and pyrazinamide, followed by 6 months of INH + RMP (2HREZ/6HR). In this report we describe treatment outcomes for 265 HIV-infected and 26 non-HIV-infected adults treated with this regimen.

STUDY POPULATION AND METHODS

Study population

Between February 1993 and July 1994, 1170 patients presenting to the National Tuberculosis Treatment Centre at Mulago Hospital, Kampala, Uganda, with suspected pulmonary tuberculosis were screened for enrolment in a prospective epidemiological study to assess the impact of TB on HIV infection. The Centre is the principal referral clinic for TB cases in the Kampala district. Subjects were eligible if they were 18–50 years old, HIV-seropositive, resided within 20 km of the clinic, had a Karnofsky performance scale score greater than 50%,14 and had normal renal and hepatic function. The Karnofsky performance scale score is a widely used indicator of the functional status of patients with chronic diseases. The physical ability of a patient to perform normal activities is scored from 0 to 100% using the scale; a score of 50% indicates that a patient is unable to care for him/herself and requires the equivalent of institutional or in-patient hospital care. Patients with previously treated TB, miliary or meningeal TB, those who were pregnant or less than 6 months post-partum, and those with advanced AIDS (World Health Organization [WHO] clinical stage IV)15 were also excluded from participation. Ten per cent of the study comprised non-HIV-infected patients to lessen the stigma attached to study subjects by assuring that participation in the study was not synonymous with HIV infection. Patients were included in the analysis if they had at least one positive sputum smear at entry and had culture-confirmed pulmonary tuberculosis.

Clinic staff performing assessments were blinded to HIV serostatus. All subjects gave informed consent before screening and enrolment in the study. The study protocol was approved by the institutional review boards of the University Hospitals of Cleveland and Case Western Reserve University and the Ugandan National AIDS Research Subcommittee.

Treatment regimen

Subjects were treated with the 8-month regimen as previously described (2 HREZ/6HR), with dosages adjusted for body weight. For subjects weighing less than 50 kg, the doses were INH 300 mg, RMP 450 mg, ethambutol (EMB) 800 mg and pyrazinamide (PZA) 1.5 g daily; for patients weighing 50–69 kg, the doses were INH 300, RMP 600 mg, EMB 1000 mg and PZA 2.0 g daily; and for patients weighing 70 kg and over, the doses were INH 300 mg, RMP 600 mg, EMB 1200 mg and PZA 2.0 g daily. Anti-tuberculosis drugs were obtained from the International Dispensary Association, the Netherlands, and manufactured under Good Manufacturing Practices. Combination tablets of INH + RMP were used whenever possible.

Treatment was given on an ambulatory basis and was not supervised. All subjects received initial health education about TB and its treatment at study entry and were counselled regarding the need to complete their treatment at each clinic visit. Patients were seen monthly at the study clinic during both the intensive and the continuation phases of treatment. Home health visitors contacted patients who failed to report for scheduled follow-up visits.

Measurements

After giving informed consent and receiving pre-HIV-test counselling, patients were screened by standardised medical history and physical examination, sputum acid-fast bacilli (AFB) smears and cultures, postero-anterior chest X-ray, HIV EIA (Recombigen HIV-1 gag + env Enzyme Immunoassay, Cambridge Bioscience, Worcester, MA), complete blood count, and serum aspartate aminotransferase (AST) and creatinine. Peripheral blood CD4 lymphocyte counts were measured using a Becton-Dickinson FACScan (Becton-Dickinson, Sparks, MD). One out of 10 HIV-positive and one out of 25 HIV-negative serum samples underwent confirmatory HIV Western immunoblot testing (Novapath HIV-1 Western Blot Kit, BioRad Nova-path, Hercules, CA).

All patients also underwent purified protein derivative (PPD) (5 tuberculin units Tubersol, Connaught, Swiftwater, PA) skin testing by the Mantoux method. Chest X-rays were taken after 1, 2, 6 and 8 months of TB treatment (end of therapy) and every 6 months thereafter, and examined for extent of disease16 and specific findings. Cavitary disease was defined as the presence of a radiolucent area greater than 1 cm in diameter surrounded by infiltrate or fibrosis.

Sputum samples were collected at baseline and after 1, 2, 6 and 8 months of TB treatment and every 6 months thereafter, as long as the patient was able to spontaneously produce sputum. Sputum smears and cultures were performed at the Uganda Tuberculosis Investigations Bacteriological Unit, Wandegeya, the National Reference Laboratory, using standard procedures. Specimens were digested with 3% NaOH, concentrated, stained by the Ziehl-Neelsen method and examined by light microscopy, and cultured on Löwenstein-Jensen slants. Cultures were incubated at 37°C in air and examined weekly until positive or for 8 weeks. Isolates were confirmed as Mycobacterium tuberculosis if the organism was nitrate positive, niacin positive, had typical colonial morphology, and growth on Middlebrook 7H-10 agar was not inhibited by 5% thiophencarboxylic acid hydrazine.

Outcomes and follow-up

Microbiologic and clinical response to treatment, survival and adverse drug reactions were the major outcomes studied. Patients were evaluated monthly during treatment and quarterly thereafter with a standardised history, physical examination and adverse event survey. Adherence to therapy was assessed by attendance at scheduled follow-up appointments, physician interview at each visit, and review of dispensing and home health visitor records.

Cure was defined as a patient confirmed to be cured on the basis of sputum microscopy and culture at the end of TB treatment. Death on treatment was defined as death from any cause while on TB treatment. Treatment failures were patients who 1) remained sputum AFB culture-positive after completion of 5 or more months of anti-tuberculosis treatment; or 2) patients with initial culture conversion but subsequent reversion to culture positivity after 5 or more months of therapy.

Relapse was defined as the development of active TB after successful completion of an initial course of treatment, as evidenced by at least two of the following: 1) development of signs and symptoms consistent with active TB; 2) chest X-ray showing a new infiltrate, cavity or effusion not present on earlier films; 3) positive sputum AFB smear; and 4) positive culture for more than five colonies of M. tuberculosis.17 Subjects who clinically responded to anti-tuberculosis chemotherapy who had fewer than five colonies of M. tuberculosis in specimens obtained later in therapy or post treatment were not considered to be relapses or treatment, failures if subsequent examinations were negative and if no clinical or radiographic deterioration was present. Such cultures were considered to be isolated positive cultures.18

Restriction fragment length polymorphism analysis

Restriction fragment length polymorphism (RFLP) analysis for the repetitive insertion sequence IS6110 of M. tuberculosis was performed at the University of Arkansas for Medical Sciences using standard procedures19 on isolates from baseline sputum samples and sputum samples collected from patients at the time of suspected relapse/recurrence. Briefly, mycobacteria were lysed and whole genomic DNA was extracted and fragmented with PvuII. The resulting DNA fragments were separated by gel electrophoresis, transferred to nitrocellulose membranes, and probed with a labelled 522-bp sequence located to the left of the PvuII site in IS6110.

Analysis

Differences between groups were compared with the χ2 or Fisher’s exact test for categorical variables and with Student’s t-test (or the appropriate non-parametric test) for continuous variables. The relapse rate was calculated as both a proportion and as an incidence rate calculated as the number of relapses divided by the total person-years of observation (PYO). All tests were two-tailed. SAS version 6.11 (SAS Institute, Cary, NC) software was used for all analyses.

RESULTS

Of the 810 cases of pulmonary tuberculosis, 470 (58%) were HIV-1 infected; 265 HIV-infected patients were enrolled. Of the 205 ineligible patients, 14 were excluded due to low Karnofsky Performance Score, 13 due to residence more than 20 km from the study clinic, 22 due to renal dysfunction, 13 due to prior TB, three due to pregnancy, 54 due to elevated serum AST, 66 due to negative sputum smear, four due to severe anaemia, and 13 due to limited ability to produce sputum for examination. Three patients declined further study participation.

Two hundred and ninety-one patients (265 HIV-infected and 26 non-HIV-infected subjects) were enrolled and started on TB treatment. The baseline characteristics of the patients are shown in Table 1. Respectively 63%, 98%, 11%, 60% and 85% of the HIV-infected patients complained of fever, productive cough, haemoptysis, chest pain and weight loss. Clinical symptoms did not differ between HIV-infected and non-HIV-infected patients. HIV-infected patients had significantly lower baseline haemoglobin and total white blood cell (WBC) counts, a lower frequency of cavitary disease and a greater prevalence of hilar or mediastinal lymphadenopathy on chest X-ray than non-HIV-infected individuals. The median CD4 lymphocyte count in the HIV-infected patients was 283 μL−1; 37% of the HIV-infected patients had a CD4 lymphocyte count less than 200 μL−1.

Table 1.

Baseline characteristics of 291 patients with initial episodes of pulmonary tuberculosis in the study cohort

Characteristic HIV-infected (n = 265) Non-HIV-infected (n = 26) P value
Male sex (%) 127 (48) 19 (73) 0.014
Age (years; mean ± SD) 29.2 ± 6.3 29.2 ± 8.8 0.97
BMI (kg/m2; mean ± SD) 19.2 ± 2.7 18.8 ± 1.9 0.33
Hemoglobin (gm/dL; mean ± SD) 10.4 ± 2.3 12.1 ± 2.1 0.0004
Total WBC count (mm3; mean ± SD) 7.5 ± 2.9 9.9 ± 2.4 0.0001
CD4 + lymphocyte count* (μL−1; median ± interquartile range) 283 (147–572)
 <200 μL−1; n (%) 94 (37)
 200–499 μL−1; n (%) 91 (36)
 >500 μL−1; n (%) 70 (27)
PPD (mm; mean ± SD) 14.6 ± 7 15.2 ± 6 0.65
Chest X-ray findings
 Radiographic severity of disease, n (%) 0.059
  Minimal disease 33 (12) 0
  Moderately advanced disease 89 (34) 5 (20)
  Far advanced disease 141 (53) 20 (80)
 Cavitary disease, n (%) 147 (55) 20 (77) 0.035
Hilar/mediastinal lymphadenopathy, n (%) 107 (40) 5 (2) 0.034
Pleural effusion/thickening, n (%) 42 (16) 3 (1) 0.567
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*

Baseline CD4 + lymphocyte counts were available for 255 HIV-infected patients.

SD = standard deviation; BMI = body mass index; WBC = white blood cells; PPD = purified protein derivative.

Adherence to clinic attendance

Thirty-four patients (11%, 31 HIV-infected and three non-HIV-infected) were lost to follow-up or defaulted on treatment, and 22 died while on treatment. Two hundred and nineteen patients attended all scheduled clinic visits during treatment, while 16 missed one or more appointments. Excluding the patients who died during treatment, 85% of all patients collected more than 80% of their drugs. The median (interquartile range) duration of follow-up was 17.7 months (12.0–24.3) for HIV-infected patients and 17.8 months (16.0–27.2) for non-HIV-infected patients. Total cumulative follow-up was 286.7 PYO for HIV-infected and 37.1 PYO for non-HIV-infected patients.

Response to anti-tuberculosis treatment

Response to treatment was monitored by serial examination, sputum microscopy and culture and chest X-ray. Table 2 shows the rate of sputum culture conversion during treatment. Seventy-three per cent of the HIV-infected patients had radiographic improvement after 2 months on treatment and 85% by 6 months compared to respectively 81% and 100% of the non-HIV-infected patients. Cough and fever had improved or resolved after 2 months’ treatment in 24% and 83% of all patients, and 97% had gained at least 3 kg by the third month of treatment (data not shown). Improvement in cough, fever and weight during treatment did not differ between HIV-infected and non-HIV-infected patients.

Table 2.

Number of patients with negative sputum cultures during successive months of anti-tuberculosis treatment

Time after onset of TB treatment (months) Total patients with sputum examined n (%) (A) Patients with only negative culture results n (%) (B) Total no. of sputum specimens examined in (B)
HIV-infected
 1 month 227 (86) 32 (14) 234
 2 months 169 (64) 160 (95) 216
 6 months 147 (55) 139 (95) 249
 8 months 130 (49) 125 (96) 250
Non-HIV-infected
 1 month 19 (73) 7 (37) 26
 2 months 15 (58) 15 (100) 15
 6 months 18 (69) 18 (100) 33
 8 months 14 (54) 13 (93) 14
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Treatment outcomes are summarised in Table 3. There were 10 (3%) treatment failures (nine HIV-infected and one non-HIV-infected). Twenty-two (8%) of the HIV-infected patients died during treatment, five within the first 2 months. The mean baseline CD4 count of the HIV-infected patients who died during treatment was 148 μL−1; three-quarters of those who died had a CD4 count <200 μL−1. None of the non-HIV-infected patients died during therapy.

Table 3.

Outcomes of anti-tuberculosis treatment

Outcome HIV-infected (n = 265) n (%) Non-HIV-infected (n = 26) n (%) P
Defaulted on treatment 31 (12) 3 (12) 0.76
Treatment failure 9 (3) 1 (4) 0.66
Died on treatment 22 (8) 0 0.26
Cured at end of treatment 203 (77) 22 (85) 0.50
Relapsed 17 (8) 1 (4) 0.83
Favourable results at the end of follow-up 183 (69) 21 (81) 0.31
Unfavourable results at the end of follow-up* 82 (31) 5 (19) 0.31
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*

Includes death at any time during follow-up, treatment failure, relapse, and patients who defaulted or were otherwise lost to follow-up.

Among the 203 HIV-infected patients who successfully completed initial TB treatment, there were a total of 17 relapses, 11 during the first year after completing treatment and six during the second year (Figure 1). The median (interquartile range) time to relapse for the HIV-infected patients was 7.2 months (4.6–13.9). The cumulative relapse rate was 8.4% and the incidence density was 5.9 per 100 PYO (95% confidence interval [CI] 3.2–8.6) during a median follow-up of 17.7 months. Twelve relapses were smear- and culture-confirmed; one subject had a positive sputum AFB smear but no positive culture, but had clinical symptoms and new radiographic findings consistent with recurrent TB; and four relapses were diagnosed based on new clinical and radiographic findings without smear or culture confirmation and an appropriate response to retreatment with anti-tuberculosis drugs. Twenty-two HIV-infected subjects who died before completing initial TB treatment, nine patients who were treatment failures, and 31 subjects who were lost to follow-up were excluded from the calculation of relapse rates.

Figure.

Figure

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Time after the end of initial anti-tuberculosis treatment until relapse. Eighteen patients relapsed (17 HIV-infected patients and one non-HIV-infected patient who relapsed 14 months after completing initial anti-tuberculosis treatment).

Among the 26 non-HIV-infected patients in the cohort, three were lost to follow-up. There was one treatment failure and one relapse in this group (cumulative relapse rate 4.5%, 2.1/100 PYO, 95%CI 0–7.8).

In the entire study cohort, relapse was associated with male sex and lower haemoglobin but not older age, HIV status, lower body mass index, or PPD reactivity (Table 4). Lower total WBC count and lower absolute CD4 lymphocyte count were more frequent in patients who relapsed (P = 0.05, t-test and P = 0.06, χ2 for trend, respectively). Sputum culture negativity after 1 and 2 months of treatment was not associated with relapse (data not shown).

Table 4.

Factors associated with relapse

Baseline characteristic Relapse (n = 18) Non-relapse (n = 207) P value
Age (years; mean ± SD) 29.5 ± 7 29.0 ± 6 0.76
Male, n (%) 13 (72) 92 (45) 0.04
HIV-infected, n (%) 17 (94) 187 (90) 0.53
BMI (kg/m2; mean ± SD) 19.2 ± 2.9 19.5 ± 2.8 0.69
PPD 16.7 ± 6 15.0 ± 7 0.68
Anergic (PPD = 0 mm), n (%) 0 7 (12%) 0.77
Total WBC (×103/mm3; mean ± SD) 6.5 ± 2.3 7.9 ± 2.9 0.05
CD4 lymphocyte count*
 <200 μL−1, n (%) 8 (47) 54 (30) 0.06
 200–500 μL−1, n (%) 8 (47) 66 (37)
 >500 μL−1, n (%) 1 (6) 59 (33)
Haemoglobin (g/dL; mean ± SD) 9.5 ± 1.9 10.8 ± 2.3 0.02
Collected ≥80% of drugs, n (%) 17 (94) 201 (97) 0.93
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*

Baseline CD4 lymphocyte counts were available for 17 patients who relapsed and 179 patients who did not relapse.

SD = standard deviation; HIV = human immunodeficiency virus; BMI = body mass index; PPD = purified protein derivative; WBC = white blood cells.

Initial sputum M. tuberculosis isolates and isolates obtained at the time of relapse were available for IS6110 DNA fingerprint analysis from three HIV-infected and one non-HIV-infected patient who relapsed. The DNA fingerprinting patterns of the initial and relapse isolates were identical in all four patients. The fingerprints of the isolates from each patient were different; each pattern consisted of more than five hybridising bands. The data indicate that each of the relapses resulted from recurrence of the organism causing the initial episode of disease and not from exogenous re-infection by another strain.

Adverse drug reactions

Adverse drug reactions occurred in 37% of the HIV-infected patients (Table 5); seven (3%) had more than one adverse reaction. Most reactions were minor and self-limiting. Only two patients, both HIV-infected, required permanent modification of their anti-tuberculosis treatment regimen due to adverse drug reactions.

Table 5.

Adverse drug reactions during anti-tuberculosis treatment

Toxicity* HIV-infected subjects n (%) Non-HIV-infected subjects n (%)
Arthralgias 59 (22) 4 (15)
Peripheral neuropathy 18 (7) 0
Skin rash 7 (3) 0
Hepatitis 2 (1) 0
GI intolerance (nausea/vomiting/diarrhoea) 2 (1) 0
Other minor reactions 10 (4) 0
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*

Categories not exclusive. Seven HIV-infected patients had more than one adverse drug reaction.

GI = gastro-intestinal.

DISCUSSION

Ambulatory treatment with a self-administered 8-month ambulatory regimen including rifampicin during the entire course of treatment was effective in a large cohort of HIV-infected Ugandan adults with initial episodes of pulmonary tuberculosis. The sputum culture conversion rate after 2 months of therapy was 95% among the HIV-infected patients who had sputum examined in our study population in which the median CD4 lymphocyte count was 283 μL−1 and over half had radiographically advanced disease with cavitation. The regimen was well tolerated, and serious adverse reactions were infrequent.

The optimal duration of treatment for HIV-infected patients with tuberculosis is an important programme issue, and has been evaluated by few comparative studies. Treatment failure rates have ranged from 0 to 6% in HIV-infected patients treated with regimens containing RMP throughout the entire course of treatment.9,20 In an earlier study by Jones et al. in the US, treatment failure occurred in 6% of 89 patients treated with a 9-month regimen and no relapses occurred during follow-up; 36% of the patients received directly observed therapy (DOT).20

Relapse rates in HIV-infected adults following 6 months of treatment with daily and intermittent RMP-based regimens have ranged from 0 to 9.9%.7,21,22 In a small US trial comparing 9 months with 6 months of supervised treatment of 101 HIV-infected adults, the relapse rate was comparable (2% vs. 3.9%, respectively).23 In a large trial done in the Democratic Republic of the Congo by Perriëns et al., 335 HIV-infected adults who completed 6 months of short-course treatment with 2HERZ/4HR were randomised to receive an additional 6 months of twice-weekly INH + RMP or placebo.8 Treatment was administered by DOT during the intensive phase of treatment, and one of two weekly doses was supervised during the continuation phase of therapy. Relapse rates were greater in HIV-infected patients treated for 6 months (9.9%) than in a non-HIV-infected control group receiving the same 6-month regimen (5.3%), although the difference was not statistically significant. The relapse rate was significantly higher, however, in HIV-infected patients receiving only 6 months (9.9%) compared to those who received 12 months (1.9%) of treatment. Treatment for 12 months was not associated with improved survival. The high relapse rate reported in the Congo study may have been due to partial supervision of treatment during the continuation phase or possibly due to relapse due to exogenous reinfection.24 The relapse rate of 8.4% (5.9/100 PYO) in our study of an 8-month regimen is intermediate between the relapse rates with 6 and 12 months of treatment in the Congo study. Studies of TB treatment in HIV-infected patients have differed due to different patient populations with varying degrees of immunosuppression, settings in areas of high and low tuberculosis transmission, whether treatment was supervised, duration, loss to follow-up, and the case definition for relapse. In aggregate, these earlier studies and the data from the current study suggest that longer durations of treatment may result in a modest decrease in relapse rates.

In our study, as in several other published reports, the relapse rate following anti-tuberculosis treatment with rifampicin-containing regimens was higher in HIV-infected than in non-HIV-infected individuals.8,25–27 Several of these studies lacked sufficient statistical power to detect a statistically significant difference between HIV-infected and non-HIV-infected patients. Recurrent tuberculosis after successful initial treatment may be due to recurrence of disease with the original M. tuberculosis strain after incomplete eradication of viable bacilli in an immunocompromised host or due to exogenous re-infection with another strain of M. tuberculosis being transmitted in the community.28,29 HIV-infected individuals are at high risk for rapid progression to active tuberculosis in the latter instance.28 Unfortunately we did not have complete DNA fingerprinting data from our patients who relapsed: in the four relapses where we did have fingerprinting data, all had recurrent disease with the same strain as the initial isolate. The mechanism of relapse in HIV-infected patients is an important area for further study, and has important implications for treatment. If most recurrences are due to exogenous re-infection, long term maintenance therapy would be more likely to be effective.30

Several baseline demographic, radiographic and microbiologic parameters and measures of response to treatment have been found to be associated with an increased risk for relapse in HIV-infected and non-HIV-infected patients (Table 6). Many of these parameters reflect the initial bacillary burden in the lung and the microbiologic response to treatment. In the current study we found that male sex was associated with an increased risk for relapse; however, initial sputum smear grade, radiographic severity of disease, and 1 and 2 month culture conversion, measures of early microbiologic response to treatment, were not associated with relapse. Lower total WBC count, absolute CD4 count and haemoglobin, all markers of more advanced HIV-related immunosuppression, were associated with relapse. The number of relapses in our study was small, however, and the data should be interpreted with caution.

Table 6.

Factors associated with relapse in pulmonary tuberculosis

Pre-HIV era HIV-infected
Younger31 or older32 age
Initial sputum viable counts (cfu)32
Initial sputum smear grade31
Initial radiographic severity and cavitary disease31
2-month sputum AFB smear negativity32
Month of sputum culture conversion32 or 2 or 3 month culture negativity31,32
Residual cavitary disease at end of treatment
Compliance31,32
Host immunological status (speculative)		 Younger (<30 years)33 or older (≥30 years)17
CD4 count <100 μL−16
Lesions in <three lung zones on initial chest X-ray33
Cutaneous reaction to thiacetazone33
Compliance17,34–36
Treatment with thiacetazone-containing regimen17,33,37–39
Treatment with rifampicin-containing regimens for <9 months6
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cfu = colony forming units; AFB = acid-fast bacilli.

In HIV-infected TB patients, adverse reactions to TB treatment have been reported in 4%–18% of patients.34,40,41 Common toxicities reported in HIV-infected patients have included skin rashes and gastrointestinal symptoms. In our study, 37% of the HIV-infected patients had adverse drug reactions which only rarely required discontinuation or permanent modification of their treatment regimen.

Our study has several important limitations. Treatment was not directly supervised in our study; however, all subjects received repeated health education regarding compliance, and defaulters were promptly traced and encouraged to resume treatment promptly. Our study population was recruited from the largest TB treatment centre in Uganda, but may not be representative of all HIV-infected Ugandan adults with tuberculosis. The median CD4 lymphocyte count in our study patients was 283 μL−1 and results with the regimen may not be as good in patients with more advanced HIV disease. Our comparison group of non-HIV-infected patients was small due to our study design. Although randomised controlled clinical trials provide the best evidence of the effectiveness of TB treatment regimens, outcomes from cohort studies assembled using explicit inclusion and exclusion criteria, rigorous outcome measures, and high follow-up rates without a direct comparison group can be compared with results from controlled clinical trials of the best standard regimens to provide useful information regarding the activity of a regimen.42 Good short-course chemotherapy regimens achieve sputum culture conversion at 2 months in more than 85% of cases, and have cure and relapse rates of more than 90% and less than 5%, respectively.43,44 The sputum culture conversion rate was 95% at 2 months in our study; however, the relapse rate was 8.4% in the HIV-infected patients. Results may not be as good using the regimen under programme conditions where resources such as defaulter tracing are not routinely used.

Tuberculosis control programmes in developing countries must balance the costs of longer durations of treatment and the likelihood of decreased compliance with longer regimens with the potential for a small decrement in relapse rates. The availability of drugs and other programme resources and the TB case-load also impact on decisions regarding the choice of first-line treatment regimens. Longer treatment should be considered on a case-by-case basis for patients with delayed clinical or microbiologic response10 or those with advanced HIV disease.

Acknowledgments

We would like to thank the patients and staff of the National Tuberculosis Treatment Centre, Mulago Hospital, the Ugandan National Tuberculosis and Leprosy Programme and the Uganda Tuberculosis Investigations Bacteriological Unit, Wandegeya, for their invaluable assistance with the conduct of this study. We also thank Dana Jankus, BS, for expert assistance with data analysis.

This work was supported by grant NO1-AI32414 (Impact of Tuberculosis on HIV Infection in Uganda) of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, USA.

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