Smear-negative pulmonary tuberculosis
Data are limited from NTP on CFR among sputum smear-negative tuberculosis patients. In Zomba, Malawi, the CFR was twice as high in smear-negative (46%) as in smear-positive (19%) tuberculosis patients . In Hlabisa, South Africa, the CFR in smear-negative tuberculosis patients increased from 13% in 1991 to 24.7% in 1995 when the HIV prevalence in women attending antenatal clinic was also increasing in the same period .
Tuberculosis CFR by HIV status
Tuberculosis (all forms)
Table 2 shows reported tuberculosis CFR among tuberculosis patients (all forms) by HIV status. Tuberculosis CFR are higher in HIV-positive than in HIV-negative patients. It is noteworthy that among HIV-negative tuberculosis patients the tuberculosis CFR is higher in high HIV prevalence populations (e.g. Malawi, Zambia) than in low HIV prevalence populations (e.g. Mali, Comoros) . In Zomba, Malawi, tuberculosis (all forms) CFR was 2.5 times higher in HIV-positive than in HIV-negative patients .
Sputum smear-positive pulmonary tuberculosis
Among patients with pulmonary tuberculosis positive by sputum smear or culture, several studies have shown a higher CFR in HIV-positive than in HIV-negative individuals (Table 3). The CFR in HIV-positive and HIV-negative patients with sputum smear-positive pulmonary tuberculosis were respectively 6.1% and 0.4% in Cote d'Ivoire , 18% and 10% in Zomba, Malawi , 29% and 8% in Ntcheu, Malawi , 14% and 0.5% in Johannesburg, South Africa , and 13% and 0% in Zaire . The lowest tuberculosis CFR in HIV-positive patients was reported in Côte d'Ivoire and should be interpreted cautiously given that one-third of the HIV-positive patients were lost to follow-up.
Sputum smear-negative pulmonary tuberculosis
A study in Malawi in patients with sputum smear-negative pulmonary tuberculosis reported a higher CFR in HIV-positive (59%) than in HIV-negative (26%) individuals . For comparison, the corresponding CFRs in sputum smear-positive patients were 18% in HIV-positive and 10% in HIV-negative patients.
When deaths occur
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].
In Hlabisa, South Africa, the probability of death for both HIV-positive and HIV-negative patients was greatest in the 2 weeks following the start of treatment. The probability of death then remained stable for HIV-negative patients at around 1% per month, whereas it continued to increase throughout the treatment period in HIV-positive patients at an average of 3% per month .
Studies in Kenya , Tanzania , and Zambia  also showed a stable probability of death in HIV-negative and an increasing probability of death in HIV-positive tuberculosis patients during and after treatment. In Kenya , the difference in probability of death between HIV-positive and HIV-negative tuberculosis patients increased between the second and the sixth month of treatment. In Tanzania 35% of HIV-positive patients died 4 years after the diagnosis of tuberculosis compared with 13% in HIV-negative tuberculosis patients . In Zambia there were five times more deaths in HIV-positive compared with HIV-negative tuberculosis patients 2 years after the start of treatment . Deaths in the later part of treatment and after the end of treatment are probably due to HIV-related causes other than tuberculosis.
The observation in the study in Kenya that death in HIV-negative patients was associated with tuberculosis symptoms of more than 2 months  suggests that early deaths may result from delay in starting treatment. The delay in initiation of tuberculosis treatment may be due to patient delay in seeking medical care, to health services failing to diagnose and initiate treatment, or to both. The local socio-economic situation and the status of the health delivery system are likely to affect patient delay in seeking medical care.
Effect of type of treatment regimen used
The type of tuberculosis treatment regimen used affects the CFR. In a study of HIV-positive tuberculosis patients in Kenya, there were no deaths reported among those who received a rifampicin-containing regimen, compared with 21 deaths among the 88 who received a non-rifampicin-containing regimen (`standard’ tuberculosis regimen comprising streptomycin, thiacetazone and isoniazid) . Other studies have also shown a higher CFR in HIV-positive tuberculosis patients treated with a non-rifampicin-containing regimen than in those treated with a rifampicin-containing regimen . Generally, the CFR in HIV-positive tuberculosis patients treated with rifampicin-containing regimens was higher among those who received rifampicin in the initial phase of treatment only compared with those who received rifampicin throughout the initial and continuation phases of treatment (see Table 3); this may be because of the protection rifampicin affords against pyogenic infections.
Findings: possible explanations for the adverse effect of HIV on tuberculosis CFR
Tuberculosis (all forms)
Biological interaction between HIV and M. tuberculosis
HIV-induced depression of cellular immunity increases the susceptibility of individuals to develop tuberculosis either from a reactivation of latent infection [35,36] or a rapid progression of a recent infection . The location and extent of tuberculosis in HIV-infected individuals depend largely on the degree of the immunosuppression, with an increased frequency of extrapulmonary and disseminated tuberculosis and lower field infiltrative pulmonary tuberculosis with more severe immunocompromise . This may increase the difficulty of diagnosis and delay the initiation of treatment, resulting in an increased risk of death. Studies have shown a strong correlation both between the severity of tuberculosis and high CFR [34,38,39], and also between severe immunosuppression and mortality [23,32]. With increased immunosuppression, patients are at increased risk of dying from HIV-related conditions such as bacteraemia and pyogenic infections .
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.
HIV interactions with anti-tuberculosis treatment
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 .
Impact of the HIV epidemic on health services
HIV infection may lead to an increased tuberculosis CFR in high HIV prevalence populations through the adverse effect of the HIV epidemic on health service delivery of care. The HIV epidemic generally increases demands on over-stretched and under-resourced health services. Over-burdening impairs health service delivery. In addition, the HIV epidemic is decreasing human resource capacity (HIV-related deaths of health care workers) and performance (decreased motivation and morale and increased absence from work through illness and attendance at funerals).
Specifically, tuberculosis control may suffer as a consequence of the demands of an increased number of tuberculosis cases due to HIV infection, usually in the face of little or no increase in resources for tuberculosis control. Consequent delays in diagnosis and initiation of treatment and decreased monitoring of tuberculosis patients may lead to their suboptimal management with an increased CFR. The increase in CFR is likely to contribute to low health worker morale and further worsening of performance.
Among HIV-negative tuberculosis patients, the higher CFR in high as compared with low HIV prevalence populations probably reflects the adverse effect of the over-burdening of health services on all tuberculosis patients.
Sputum smear-negative pulmonary tuberculosis
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).
Misdiagnosis of other HIV-related diseases as sputum smear-negative pulmonary tuberculosis is also a likely explanation for the higher CFR in sputum smear-negative than in sputum smear-positive pulmonary tuberculosis patients in high HIV prevalence populations. In addition, the higher HIV seroprevalence in smear-negative than in smear-positive patients is likely to result in a correspondingly higher risk of death due to HIV-related illnesses other than tuberculosis, e.g. bacteraemia.
Findings: causes of death in HIV-positive tuberculosis patients
The two main sources of information on the causes of death in HIV-positive tuberculosis patients are from a limited number of post-mortem and clinical/microbiological studies. Post-mortem examinations are not routinely performed in most countries in sub-Saharan Africa. The general assumption is that deaths are usually due to HIV-related diseases other than tuberculosis. A study in Kenya using verbal autopsies reported that the proportion of deaths due to causes other than tuberculosis was greater in HIV-positive (23%) than HIV-negative patients (0%) .
Two studies have reported data on post-mortem examinations of tuberculosis patients. A post-mortem study of tuberculosis patients in Abidjan showed that tuberculosis was the primary cause of death in two out of five smear-positive HIV-positive patients who died during tuberculosis treatment . Opportunistic infections other than tuberculosis were the only causes of death in patients with sputum smear-positive pulmonary tuberculosis who died after completion of treatment. In a study in South Africa, post-mortem examinations performed in half of a group of patients with sputum smear-positive pulmonary tuberculosis showed that five of the six deaths that occurred within the first month of treatment were caused by tuberculosis, whereas late deaths were most commonly due to opportunistic infections such as cryptococcal pneumonia . The main limitation of these studies is the small number of cases examined. There is an urgent need for more studies to determine the cause of death in tuberculosis patients, in order to clarify the relative contributions of death from HIV-related diseases other than tuberculosis and failure of mycobacterial response to anti-tuberculosis treatment.
Two studies conducted in Africa have looked at the cause of death of HIV-positive patients basing their finding on clinical data collected on patients before their death. The study in Kinshasa considered that 25 of the 90 deaths (28%), which occurred in HIV–tuberculosis individuals were related to tuberculosis compared with one of the four HIV-negative patients who died . In Zambia, tuberculosis was responsible for the death of 14 out of 42 (33%) HIV-positive individuals and three out of five (60%) HIV-negative patients .
Conclusion: measures to decrease the tuberculosis CFR in high HIV prevalence populations
General measures in improving health services and specific measures are needed to counter high tuberculosis CFRs.
Health service measures
Improved general health services
General measures needed to counter high tuberculosis CFR include increased investment in improving health services and infrastructure capable of responding to increased HIV-related health needs, including tuberculosis control.
Improved tuberculosis control services
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.
Improved HIV control
Controlling tuberculosis in high HIV prevalence populations will require effective HIV control measures. The implementation of measures to decrease HIV transmission is likely to not only decrease tuberculosis incidence but also to decrease the tuberculosis CFR.
Improved collaboration between tuberculosis and HIV services
The organization of care provision for tuberculosis patients must ensure the prompt diagnosis and treatment of other HIV-related diseases. This will require close collaboration between NTP and National AIDS Control Programs.
Preventive treatment of HIV-related causes of death other than tuberculosis
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 .
Studies in low tuberculosis prevalence populations have shown that highly active anti-retroviral therapy (HAART) decreases mortality in HIV-positive patients [54,55]. The provision of HAART to HIV-positive tuberculosis patients in high tuberculosis prevalence populations may result in a decreased tuberculosis CFR. However, current prospects for widespread use of HAART in sub-Saharan Africa are poor because of the generally weak health service infrastructure, prohibitively expensive drugs, lack of monitoring capacity, and difficulties in maintaining regular drug supplies and ensuring adherence to complex treatment regimens.
Immune modulation and micronutrient supplementation
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.
Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Tuberculosis; HIV; mortality; sub-Saharan Africa