Survival analyses in several studies have shown that the timing of deaths differed between HIV-positive and HIV-negative groups [11,22,23,27]. Fig. 3 shows a Kaplan–Meier survival curve for HIV-positive and HIV-negative tuberculosis patients in a study in Kenya . A study in Uganda described a biphasic distribution of deaths in HIV-positive patients, with the first peak of risk of death being reached within the first 3 months of treatment, and a second peak around the 21st month after first starting treatment . Most other studies have reported a similar bimodal distribution [11,22,23,27].
Immunological and virological studies indicate that the host's immune response to M. tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection. There is evidence that the lungs of HIV-positive tuberculosis patients have more signs of HIV replication than those of HIV-positive individuals without tuberculosis . This supports the hypothesis that pulmonary tuberculosis enhances local replication of HIV. Cohort studies reported shorter survival among HIV-positive tuberculosis patients than among HIV-positive patients without tuberculosis [42–45]. Thus tuberculosis accelerates the course of HIV infection and enhances the suppression of cellular immunity, which is strongly associated with death.
Although no longer on the list of drugs recommended by WHO for use as part of anti-tuberculosis treatment regimens , thiacetazone is still in use in some high HIV prevalence populations and may contribute to excess tuberculosis deaths on account of the increased risk of severe and sometimes fatal drug reactions. Decreased gut absorption of anti-tuberculosis drugs could lead to decreased effectiveness of treatment regimens and impaired treatment outcomes, including death, in HIV-positive tuberculosis patients. Some studies (although not on patients in high tuberculosis prevalence populations) have shown decreased gut absorption of anti-tuberculosis drugs in HIV-positive tuberculosis patients [46,47], but another study found no evidence that HIV infection reduced plasma concentrations of anti-tuberculosis drugs .
With often hard-pressed diagnostic services, misdiagnosis may at least partly account for the high CFR in sputum smear-negative tuberculosis patients. Firstly, new sputum smear-positive patients (category 1, see WHO classification of tuberculosis patients ) may be misdiagnosed as sputum smear-negative (category 3), and under-treated with the category 3 regimen. Secondly, because there is no ‘gold standard’ diagnostic test for smear-negative patients, the tuberculosis CFR in smear-negative patients represents a mix of deaths from tuberculosis and other diseases misdiagnosed as tuberculosis. These include diseases related to HIV (e.g. Pneumocystis carinii pneumonia) and diseases unrelated to HIV (e.g. heart failure).
General measures in improving health services and specific measures are needed to counter high tuberculosis CFRs.
In addition to strengthening the general health services and infrastructure, specific investment is needed to improve tuberculosis control services, to ensure access of all tuberculosis patients to prompt diagnosis and initiation of safe and effective treatment and the necessary support for patients to complete treatment. There is a need for studies to establish the effectiveness, affordability and cost-effectiveness of targeted screening of high-risk groups to promote the prompt identification of sputum-positive cases, in addition to the current policy of screening of respiratory symptomatics presenting to general health services. Policy-makers in the international agencies and national governments need to consider whether all HIV-positive tuberculosis patients should receive a 6-month treatment regimen containing rifampicin throughout rather than an 8-month regimen containing rifampicin in the initial phase only. In view of the importance of preserving the efficacy of rifampicin as the most potent anti-tuberculosis drug currently available, international recommendations are needed for direct observation of rifampicin whether given in the initial or continuation phase of treatment . Policy-makers need to be aware of the considerable extra resources necessary to ensure direct observation throughout the 6 months of treatment.
Two randomized controlled trials in Côte d'Ivoire comparing cotrimoxazole preventive treatment and placebo in HIV-positive patients showed a lower incidence of bacterial infections in the cotrimoxazole group [50,51]. The study which enrolled HIV-positive patients with sputum smear-positive pulmonary tuberculosis reported a significantly decreased (46%) tuberculosis CFR in patients treated with cotrimoxazole . A study in Cape Town, South Africa, similarly showed improved survival among HIV-positive tuberculosis patients receiving cotrimoxazole prophylaxis compared with placebo . Although UNAIDS and WHO have recommended the use of cotrimoxazole prophylaxis in HIV-infected adults and children in Africa as part of a minimum package of care, this still requires further evaluation of affordability, feasibility and acceptability in a range of different settings .
The results of clinical trials have not confirmed the earlier hopes that immune modulation through the use of M. vaccae might prove beneficial to the outcome of treatment of tuberculosis patients . The possible beneficial role of vitamin A supplementation is under evaluation in tuberculosis patients in high HIV prevalence populations.
1. Maher D, Chaulet P, Spinaci S, Harries A. Treatment of Tuberculosis: Guidelines for National Programmes. 2nd edn,
Geneva: World Health Organization; 1997. WHO/TB/97.220.
2. Enarson DA, Rider HL, Arnadottir T, Trebucq A. Management of Tuberculosis. A Guide for Low-Income Countries. 5th edn, Paris: International Union Against Tuberculosis and Lung Disease (IUATLD)
3. Beaglehole R, Bonita R, Kjellstrom T. Basic Epidemiology.
Geneve: World Health Organization; 1993.
4. Harries AD, Maher D. TB/HIV: A Clinical Manual.
Geneva: World Health Organization; 1996. WHO/TB/96.200.
5. Buhl K, Nyboe J. Epidemiological basis of tuberculosis eradication.
:Changes in the mortality of Danish tuberculosis patients since 1925.
Bull World Health Org 1967, 37: 907 –925.
6. Thompson BC. Survival rates in pulmonary tuberculosis
. BMJ 1943, 2: 721. 721.
7. Styblo K. Epidemiology of tuberculosis.
In:Royal Netherlands Tuberculosis Association (KNCV) selected papers
in Kenya: follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. An East African and British Medical Research Council co-operative investigation. Tubercle
9. Malkin JE, Prazuck T, Simonet F. et al. Tuberculosis and human immunodeficiency virus infection in West Burkina Faso: Clinical presentation and clinical evolution.
Int J Tuberc Lung Dis 1997, 1: 68 –74.
10. Perriens JH, Colebunders RL, Karahunga C. et al. Increased mortality and tuberculosis treatment failure rate among human imunodeficiency virus (HIV) seropositive compared with HIV seronegative patients with pulmonary tuberculosis treated with standard chemotherapy in Kinshasa, Zaire.
Am Rev Respir Dis 1991, 144: 750 –755.
11. Elliott AM, Halwiindi B, Hayes RJ. et al. The impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in Zambia.
Trans Roy Soc Trop Med Hyg 1995, 89: 78 –82.
12. Garin B, Glaziou P, Kassa-Kelembho E, Yassibanda S, Mbelesso P, Morvan J. High mortality rates among patients with tuberculosis in Bangui, Central African Republic.
Lancet 1997, 350: 1298. 1298.
13. Banerjee A, Moyo S, Salaniponi F, Harries A. HIV testing and tuberculosis outcome in a rural district in Malawi.
Trans Roy Soc Trop Med 1997, 91: 707 –708.
14. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000.
Bull World Health Org 1994, 72: 213 –220.
15. World Health Organization. Communicable Diseases Cluster. Global Tuberculosis Control report. WHO report 2000, WHO/CDS/TB/2000.275
16. Joint United Nations Programme on HIV
/AIDS. eport on the global HIV/AIDS epidemic – June 2000. UNAIDS report 2000. UNAIDS/00.13E
17. Dye C, Scheele S, Dolin P, Pathania V, Raviglione M. Global burden of tuberculosis: Estimated incidence, prevalence, and mortality by country.
JAMA 1999, 282: 677 –686.
18. Moorman J, Edgington M. Cause of death of patients on treatment for tuberculosis: a study in a rural South African Hospital.
Int J Tuberc Lung Dis 1999, 3: 786 –790.
19. Kruyt ML, Kruyt ND, Boeree MJ, Harries AD, Salaniponi FM, van Noord PA. True status of smear-positive pulmonary tuberculosis defaulters in Malawi.
Bull World Health Org 1999, 77: 386 –391.
20. Harries AD, Nyangulu DS, Kang'ombe C. et al. Treatment outcome of unselected cohort of tuberculosis patients in relation to human immunodefeciency virus serostatus in Zomba hospital, Malawi
. Trans Roy Soc Trop Med 1998, 92: 343 –347.
21. Connolly C, Davies GR, Wilkinson D. Impact of the human immunodeficiency virus epidemic on mortality among adults with tuberculosis in rural South Africa, 1991–1995.
Int J Tuberc Lung Dis 1998, 2: 919 –925.
22. van den Broek, Mfinanga S, Moshiro C, O'Brien R, Mugomela A, Lefi M. Impact of human immunodeficiency virus infection on the outcome of treatment and survival of tuberculosis patients in Mwanza, Tanzania.
Int J Tuberc Lung Dis 1998, 2: 547 –552.
23. Nunn P, Brindle R, Carpenter L. et al. Cohort study of human immunodeficiency virus infection in patients with tuberculosis in Nairobi, Kenya.
:Analysis of early (6-month) mortality.
Am Rev Respir Dis 1992, 146: 849 –854.
24. Wilkinson D, Moore DA. HIV-related tuberculosis in South Africa - clinical features and outcome.
S Afr Med J 1996, 86: 64 –67.
25. Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett P. Human immunodeficiency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients.
Am J Respir Crit Care Med 1999, 159: 733 –740.
26. Perriens JH, St. Louis ME, Mukadi YB. et al. Pulmonary tuberculosis in HIV-infected patients in Zaire.
:A controlled trial of treatment for either 6 to 12 months.
N Engl J Med 1995, 332: 779 –784.
27. Kassim S, Sassan-Morokro M, Ackah A. et al. Two-year follow-up of persons with HIV-1- and HIV-2-associated pulmonary tuberculosis treated with short-course chemotherapy in West Africa.
AIDS 1995, 9: 1185 –1191.
28. Kool HE, Bloemkolk D, Reeve PA, Danner SA. HIV seropositivity and tuberculosis in a large general hospital in Malawi.
Trop Geogr Med 1990, 42: 128 –132.
29. Kelly P, Burnham G, Radford C. HIV seropositivity and tuberculosis in a rural Malawi hospital.
Trans Roy Soc Trop Med Hyg 1990, 84: 725 –727.
30. Kelly PM, Cummings RG, Kaldor JM. HIV and tuberculosis in rural sub-Saharan Africa: a cohort study with two year follow-up.
Trans Roy Soc Trop Med Hyg 1999, 93: 287 –293.
31. Harries AD, Maher D, Mvula B, Nyangulu DS. An audit of HIV testing and HIV serostatus in tuberculosis patients, Blantyre, Malawi.
Tuberc Lung Dis 1995, 76: 413 –417.
32. Ackah AN, Coulibaly D, Digbeu H. et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Côte d'Ivoire.
Lancet 1995, 345: 607 –610.
33. Whalen C, Okwera A, Johnson M. et al. Predictors of survival in human immunodeficiency virus-infected patients with pulmonary tuberculosis.
Am J Respir Crit Care Med 1996, 153: 1977 –1981.
34. Elliott AM, Halwiindi B, Hayes RJ. et al. The impact of human immunodeficiency virus on response to treatment and recurrence rate in patients treated for tuberculosis: two-year follow-up of a cohort in Lusaka, Zambia.
J Trop Med Hyg 1995, 98: 9 –21.
35. Selwyn PA, Hartel D, Lewis VA. et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection.
N Engl J Med 1989, 320: 545 –550.
36. Braun MM, Badi N, Ryder RW. et al. A retrospective cohort study of the risk of tuberculosis among women of childbearing age with HIV infection in Zaire.
Am Rev Respir Dis 1991, 143: 501 –504.
37. Daley CL, Small PM, Schecter GF. et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus.
:An analysis using restriction-fragment-length polymorphisms.
N Engl J Med 1992, 326: 231 –235.
38. De Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa.
JAMA 1992, 268: 1581 –1587.
39. Abouya YL, Beaumel A, Lucas S. et al. Pneumocystis carinii pneumonia.
:An uncommon cause of death in African patients with acquired immunodeficiency syndrome.
Am Rev Respir Dis 1992, 145: 617 –620.
40. Lucas SB, Hounnou A, Peacock C. et al. The mortality and pathology of HIV infection in a West African city.
AIDS 1993, 7: 1569 –1579.
41. Nakata K, Rom WN, Honda Y. et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung.
Am J Respir Crit Care Med 1997, 155: 996 –1003.
42. Whalen C, Horsburgh CR, Hom D. et al. Accelerated course of human immunodeficiency virus infection after tuberculosis.
Am J Respir Crit Care Med 1995, 151: 129 –135.
43. Whalen C, Horsburgh CR, Hom D. et al. Site of disease and opportunistic infection predict survival in HIV-associated tuberculosis.
AIDS 1997, 11: 455 –460.
44. Leroy V, Salmi LR, Dupon M. et al. Progression of human immunodeficiency virus infection in patients with tuberculosis disease.
Am J Epidemiol 1997, 145: 293 –300.
45. Whalen C, Nsubuga P, Okwera A. et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda.
AIDS 2000, 14: 1219 –1228.
46. Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial medications.
N Engl J Med 1993, 329: 1122 –1123.
47. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antituberculosis medications by a patient with AIDS.
N Engl J Med 1992, 327: 1817 –1818.
48. Taylor B, Smith PJ. Does AIDS impair the absorption of antituberculosis agents?
Int J Tuberc Lung Dis 1998, 2: 670 –675.
49. Greenberg AE, Lucas S, Tossou O. et al. Autopsy-proven causes of death in HIV-infected patients treated for tuberculosis in Abidjan, Côte d'Ivoire.
AIDS 1995, 9: 1251 –1254.
50. Wiktor SZ, Sassan-Morokro M, Grant AD. et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d'Ivoire: a randomised controlled trial.
Lancet 1999, 353: 1469 –1475.
51. Anglaret X, Chene G, Attia A. et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial.
Lancet 1999, 353: 1463 –1468.
52. Badri M, Maartens G, Wood R, Ehrlich R. Co-trimoxazole in HIV-1 infection.
Lancet 1999, 354: 334 –335.
53. United Nations Joint Programme on AIDS and World Health Organization. Provisional WHO/UNAIDS secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living with HIV
/AIDS in Africa as part of a minimum package of care.
54. Mocroft A, Vella S, Benfield TL. et al. Changing patterns of mortality across Europe in patients infected with HIV-1.
:EuroSIDA Study Group.
Lancet 1998, 352: 1725 –1730.
55. Palella FJ Jr, Delaney KM, Moorman AC. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.
:HIV Outpatient Study Investigators.
N Engl J Med 1998, 338: 853 –860.
56. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial.
Lancet 1999, 354: 116 –119.