Tuberculosis and HIV infection association in a rural district of Northern Uganda: epidemiological and clinical considerations G. B. Mi liori, A. Borghesi*, C. Adrikot, Acocella ! +

V. Manfrin *, S. Okwaret,

W. Naamaras,

A. Bartoloni**,

M. Neri, G.

Clinica de1 Lavoro Foundation, Care and Research Institute, Department of Pneumology, Tradate Medical Centre, ltaly, *Development Cooperation General Direction, Health Section, Ministry of Foreign Affairs, Italy, iDM0 Arua District, Uganda, *Director AIDS Control Programme, Uganda, $ WHO/ACP, Uganda, **Chair of 1rtfectiou.s Diseases, University of Florence, Italy, TtReference Centre for Chemotheraphy, University gf Pavia. Ituly 59 (18.3%) of 323 patients with tuberculosis (TB) tested for HIV-l antibody by ELISA technique (Wellcozyme) were seropositive. In the control group selected among the health personnel working in the Arua Hospital, 7.7% were found positive for HIV-l antibody, thus showing a significantly lower prevalence compared with the TB patients (P c 0.005). The prevalence of HIV infection was 50% in the urban TB patients, 7% in TB patients living in rural areas surrounding Arua town and 1.6% in the peripheral rural setting. Of 27 TB patients with clinical AIDS, 18 died during the course of the study. The AIDS patients’ survival rate was 46.4% 6 months after diagnosis, and 21.4% after 16 months, the median period of survival being 5.0 months. Risk factors, sputum conversion rate, clinical and radiological findings were analysed. No significant difference was found between seropositive and seronegative TB patients for clinical drug-related toxicity (P > 0.05). S UM MA R Y.

R 6s UMf?. 59 de 323 malades (l&3%) atteints de tuberculose (TB) et testes pour l’antigene VIH-1 par la technique ELISA (Wellcozyme) etaient seropositifs. Dans le groupe temoin, choisi parmi le personnel medical travaillant a l’hbpital d’Arua, 7,7% Ctaient positifs pour l’antigene VIH-1, soit une prevalence significativement plus basse par rapport aux malades atteints de tuberculose (PcO,OO5).La prevalence de l’infection par le VIH Ctait de 50% chez les malades tuberculeux de zone urhaine, de 7% chez les malades tuberculeux de zone rurale, sit&e autour de la ville d’iirua, et de 1,6% dans les zones rurales excentrees. De 27 malades atteints de SIDA clinique, 18 sont morts au tours de l’etude. Le taux de survie parmi les malades atteints de SIDA Ctait de 46,4% six mois apres le diagnostic et 21,4% apres 16 mois; la mediane &ant de 5,0 mois. Les facteurs de risque, le taux de conversion des crachats, les constatations cliniques et radiologiques ont CtCCvaluCes.Aucune difference n’a i3tetrouvee entre les malades tuberculeux seropositifs et seronegatifs quant a une toxicite like aux drogues cliniques (P > 0,05). R ES UM E N. De un total de 323 pacientes con tuberculosis (TB), sometidos a test para el anticuerpo VIH-1

con la tbnica ELISA (Wellcozyme), 59 (18,3 %) eran seropositivos. En el grupo control seleccionado entre el personal sano de1 Hospital Arua, un 7,7 % era seropositivo para el anticuerpo HIV-l, lo que muestra una prevalencia significativamente mas baja, comparado con la de 10s pacientes TB (P 0,05).

Correspondence to: Dr G. B. Migliori, Fondazione Via Roncaccio 16/18, 21049 Tradate WA), Italy.

Clinica de1 Lavoro.

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INTRODUCTION Tuberculosis associated with HIV-l infection has been described by several authors in the past few years, the HIV seropositivity ranging from 10 to 55% of the TB patients according to different studies.‘” Tuberculosis in HIVinfected patients often indicates a reactivation of latent infection rather than a primary tuberculous infection.7-8 The role of HIV infection in promoting progression of primary TB infection to active disease is well known.9 Consequently, the incidence of tuberculosis in HIVinfected patients can be expected to be higher in populations of geographic areas such as central Africa, where high prevalence of HIV and tuberculous infection may coexist6 The present study was carried out in the rural district of Arua, Northern Uganda, where the risk of TB infections is estimated to be 2% per annum and the number of notified AIDS cases was below 1 per 100 000 inhabitants (cumulative incidence as of 31 July 1988).“~” The prevalence of HIV infection in the district is not yet available. The aim of the present study was to evaluate the TB/HIV-associated infections in a group of patients diagnosed as having TB at Arua Regional Hospital in terms of risk factors and clinical outcome (sputum conversion rate, tuberculin reactivity, survival time, radiological features, associated infections, response to treatment, drug-related toxicity).

STUDY POPULATION

AND METHODS

All of the TB patients diagnosed at Arua Hospital from 1 June 1987 to 30 August 1989 were enrolled in the study. The diagnosis of tuberculosis was made when the patients met at least one of the following criteria:’ 1. Sputum examination positive for alcohol acid-fast bacilli (AAFB) stained according to the ZiehlNielsen method. 2. Gastric lavage fluid positive for AAFB (see above). 3. Histological examination suggestive of TB. 4. X-ray suggestive of pulmonary or bone TB. We considered as bacteriologically confirmed cases the patients with positive gastric lavage on the basis of satisfactory results obtained in our previous study.12 All TB patients were tested for anti-HIV- 1 antibody by ELISA technique (Wellcozyme) at the Uganda Virus Research Institute; positive results were confirmed by a second assay. A patient was considered HIV-infected if the test was positive on at least two separate determinations.*.3,‘1,‘3 In Uganda sensitivity and specificity of the Wellcozyme ELISA were assessed to be respectively 90 and 96%:13 a patient was considered to have AIDS if he met the Uganda Modified Clinical Case

Definition, excluding cough as a minor sign in presence of TB (sensitivity 52%; specificity 92%).3 Children more than 15 months old with repeated positive tests were considered HIV-infected. Seropositive children meeting the provisional WHO case definition for pediatric AIDS in the absence of known causes of immunosuppression were considered AIDS cases.14 All patients had at least 3 sputum or gastric lavage tests for AAFB and were reviewed after 2 months of treatment. If they were still positive after 2 months, tests for AAFB were continued monthly until sputum conversion had taken place. All subjects were tested with 2 TU of PPD RT 23, Copenhagen, with Tween 80; all seropositive subjects were X-rayed on admission and, later, according to clinical need.‘,” It was not possible to systematically perform X-ray examinations on all seronegative patients for lack of film. The diagnosis of oral and oropharyngeal candidiasis was done on a clinical basis only.’ Patients were treated with thiacetazone (T; 25 mg/kg of body weight/day) and isoniazid (I; 5 mg/kg of body weight/day) in combined tablets for 10 months, supplemented by streptomycin (S; 20 mg/kg of body weight/day) for the intensive phase (first 2 months of treatment). In cases of treatment failure (sputum-positive after 6 months of regular T-I-S treatment), a second line 9-month regimen was administered, consisting of rifampicin (10 mg/kg of body weight/day), ethambutol(25 mgkg of body weight/day) and isoniazid (5 mg/kg of body weight/day). Thiacetazone-induced toxicity was proved by suspending the combined tablets. After the resolution of toxic symptoms (mainly exfoliative dermatitis), treatment continued with isoniazid alone at increasing dosages; after reaching the dose of 5 mg/kg of body weight/day, if no side-effects appeared, a second drug different from thiacetazone was added (ethambutol).‘6 The analysis was carried out considering as the group 59 seropositive tuberculosis patients and as controls 264 seronegative tuberculosis patients. To evaluate the difference in seropositivity rate between TB and non-TB patients, a comparison was carried out between all tuberculosis patients (n = 323) and a control group selected among the healthy personnel of Arua Hospital (n = 116). These were mainly manual workers without any occupational risk for HIV infection; all wer tested for HIV- 1 antibody. Statistical analysis was carried out using the 2 x 2 contingency tables with chi-square test: (Yates corrected or Fisher’s exact tests where appropriate). A P value < 0.05 was considered significant.

RESULTS Epidemiology 59 (18.3%) TB patients were found HIV-positive, while in the control group the positivity rate was 7.7% (9 of

TBC and HIV infection association Table 1. Age and sex distribution of 59 HIV-l positive TB patients and 264 HIV- 1 negative TB patients (Arua district, Uganda)

Age

HIV- 1 Positive Males Females

44 Total

5 0 8 20 6 3 42

2 0 8 4 0 2 17

Mean Median Mode SD

27.69 29 30 12.996

23 22 18 13.869

Student’s t-test (two tailed, non-paired)

NS (P>O.2)

HIV- 1 Negative Males Females 15 9 19 33 23 47 146

13 10 20 21 24 24 118

24.33 21 15 13.721

19.66 22 24 6.772

NS (fiO.4)

116 subjects) (P < 0.005). Five of the 9 positive subjects employed at Arua Hospital were manual workers. We had 42 males (71.2%) and 17 females (28.8%) in the HIV-seropositive group, and 145 males (54.9%) and 119 females (45.1%) in the HIV-seronegative group (P < 0.05). The mean age of the seropositive males was 27.69 + 12.9 years (33.62 among seronegatives) and that of the seropositive females was 23.00 f 13.9 (28.46 among seronegatives). A comparison between the mean age of seropositive males and females does not appear to be significant (ttest; P > 0.05; Table 1). Most of the HIV-positive patients (n = 46; 78%) lived in Arua town, 12 (20.3%) in the rural areas surrounding Arua and 1 (1.7%) in peripheral rural settings, near Omugo Health Centre, a peripheral TB unit covering a rural area near the district border. The prevalence of the combined HIV/TB infection was 50% (46 of 92) in the patients living in the town, 7% (12 of 171) in the patients living in the rural areas surrounding Arua and 1.6% (1 of 61) in the patients living in the peripheral setting (P < 0.0001). The risk factors identified are shown in Table 2. 28 patients had sexually transmitted diseases (STDs), represented by episodes of gonorrhoea, syphilis and chancroid (P < 0.0001; 0 R 6.32, considering all the

Table 2.

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different kinds of STDs). Gonorrhoea occurred more commonly among seropositives (25 out of 59) than among seronegatives (33 out of 264; P < 0.0001). 16 seropositive patients had had 5-9 sexual partners in the last 2 years, 4 patients had had lo-14,4 had had 15-19, and 5 more than 20 (P < 0.0001 for more than 5 sexual partners). The mean number of sexual partners among seropositives was 10.6. Active and passive prostitution, distinguished by payment given or received for sexual intercourse, and history of previous blood transfusions appear statistically significant (P < 0.05). Skin piercing was more common in seronegative patients than in seropositives (56.8% v,s 30.5%; P < 0.0005). Of the 168 TB patients who had practised skin piercing, 103 were rural residents (6 HIV-infected, 5.8%) and 65 were living in urban areas (12 HIV-infected, 18.5% P < 0.05). Soldiers, drivers and businessmen did not seem to be groups at risk (P > 0.05) compared with other studies,” probably because of the very minor number of these subjects comprised in our study. The comparison of risk factors gave similar results when performed for bacteriologically confirmed seropositive and seronegative TB patients or for all cases. The injections outside the health unit do not appear to be significant predictors.

Clinical considerations The complete medical history was available for 53 (89.8%) of the seropositive patients (6 patients defaulted treatment). 35 seropositive TB patients are still alive, 10 with AIDS. Clinical AIDS was present in 28 TB patients (9 had AIDS already at the first visit). In 2 patients seropositivity appeared 7 and 9 months, respectively. after the diagnosis of TB. 54 of the TB seropositive patients had pulmonary TB (91.5%), 4 lymph node TB and 1 osteoarticular TB. In the seronegative TB group 239 had pulmonary TB (90.5%), 14 osteoarticular, 7 lymph node, 2 enteric, I meningeal and 1 genitourinary TB; no significant difference was found between seropositives and seronegatives (Table 3). Among the 51 seropositive patients completely followed up, 36 (70.6%) sputum converted within the

Risk factors involved in HIV-l infection in 323 TB patients (Arua District, Uganda)

Risk factor

HIV- 1 positive TB patients

STDs >5 partners Money given/ received for sex Blood transfusion Skin piercing Injections not in Health Unit

28 (47.4%) 21 (35.6%)

33 (12.5%) 25 (9.5%)

0.05

31119 (2.5%) 261264 (9.8%) 91264 (3.4%) 231264 (8.7%)

0.05

months

Weight loss >lO% Diarrhoea>l

first 2 months, 6 (11.8%) during the third and 3 (5.9%) during the fourth month; 4 (7.8%) died before sputum conversion, 2 (3.9%) had treatment failure (remained positive). In the 197 seronegative patients, 134 (68%) converted within the first 2 months, 34 (17.3%) during the third, 19 (9.7%) during the fourth, and 2 (1%) during the fifth, 4 (2%) defaulted before sputum conversion, and 4 (2%) had treatment failure. Six patients with treatment failure were given second line treatment with sputum conversion within 2 months. There were no differences between the two groups concerning sputum conversion rate or treatment failure in response to the first line treatment (P > 0.05). Other symptoms, such as long-lasting cough, amenorrhoea and weight loss are described in Table 4. The proportion with positive Mantoux reactions was significantly lower in the seropositive group (66.1% compared to 82.2% in the seronegative group; P < 0.01). The rate of toxic reactions was high in both groups, without statistically significant differences (the average rate of major toxic reactions was 9.9%). Four patients died from side-effects. Two children (one of them HIVpositive) died from Stevens-Johnson syndrome, while a seronegative child and a seropositive adult died from toxic hepatitis. Amongst the AIDS patients we noticed 11 episodes of intercurrent chest infection (6 were bilateral interstitial infiltrates) and 18 episodes of severe diarrhoea. The stool examination performed on the patients with diarrhoea resulted negative for intestinal parasites or non-pathogenic protozoa in 6 cases, 2 of which improved with 10 days of sulphamethoxazole-trimethoprim treatment. In the other patients we found Ascaris lumbricoides (4 cases), Entamoeba coli (4 cases), Strongyloides stercoralis (3 cases) and Giardia intestinaks (1 case). The fatality rate was 30.5% (18 of 59) among seropositives and 8.7% (23 of 264) among seronegatives (P < 0.0001). The differences were similar when considering separately the bacteriologically confirmed cases. The cure rate for TB was 42.4% (25 of 59) in the first and 49.2% (130 of 264) in the second group (P > 0.05). The difference between seropositives and seronegatives in the bacteriologically confirmed cases (25/54 vs 126/178, respectively; P > 0.05) appears not to be significant.

Fevenl

month

month

Oral thrush Skin rash Lymph adenopathy $Amenotrhoea Major toxic reactions Thiacetazoneinduced toxicity Death while on treatment *Calculations Calculations *Calculations

P value

>0.05 0.05). TB was diagnosed earlier (within 4 months from the onset of the cough) in seropositive patients (P < O.OOl), the reason probably being an accelerated natural history of TB in immunocompromised persons. Amenorrhoea is a confirmed sentinel sign for HIV infection;” in our study it was found in 3 of 5 fertile women with AIDS, only 1 presenting a weight loss of more than 20%. The clinical response to the standard treatment (2 STVlO TI) was the same in seropositive and seronegative subjects, as confirmed by the similar TB cure rates found in the two groups (42.4% and 49.2%, respectively). As far as toxic reactions are concerned we found no significant difference between the two groups studied with an average toxic reaction rate of 9.9%, higher than

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that reported in some other studies.‘~“~” We did not observe the considerable toxicity reported by Colebunders et al5 and E&i et a$ in seropositive TB patients. The difference could be explained by genetic differences in the population examined. Our study was performed in a northern region of Uganda where two tribes (Kakwa and Lugbara) of Nilotic origin are prevalent. The standard ST1 regimen, with all its limitations, continues to be used for treatment of HIV-positive TB patients in developing countries,24 until improved economic conditions will allow the adoption of regimens with higher cure rates. Because of relatively high HIV seroprevalence, TB patients should be used as sentinel populations to detect HIV-related illnesses in selected areas. The contemporary development of TB/AIDS control programmes allowed us monthly follow-up of the HIV-positive patients with TB without further problems. This connection is essential for carrying out longitudinal studies in East Africa.

Acknowledgements The authors wish to thank Ing. Luigi Ballardini and Emanuela Radice (Statistics Department, Clinica de1 Lavoro Foundation, Tradate) for their considerable help in the data analysis.

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20. Rothemberg R. Survival with acquired immunodeficiency syndrome. N Engl J Med 1987; 317: 1297-1302. 21. Holdiness M R. Adverse cutaneous reaction to antituberculosis drugs. Int J Dermatol 1985; 24: 280-285. 22. Pinching E J. The acquired immune deficiency syndrome: with special reference to tuberculosis. Tubercle 1987; 68: 65-69. 23. E&i P P, Okwera A, Aisu T, Morrissey A B, Ellner J J, Daniel T M. The influence of human immunodeficiency virus infection on tuberculosis in Kampala, Uganda. Am Rev Respir Dis 1991; 143: 185-187. 24. Centers for Disease Control: Tuberculosis and acquired immunodeficiency syndrome - New York City. MMWR 1987; 36: 785-795.

Tuberculosis and HIV infection association in a rural district of northern Uganda: epidemiological and clinical considerations.

59 (18.3%) of 323 patients with tuberculosis (TB) tested for HIV-1 antibody by ELISA technique (Wellcozyme) were seropositive. In the control group se...
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