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.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Tuberculosis; HIV; mortality; sub-Saharan Africa