During the course of the AIDS pandemic, we learned a considerable amount about the intersection of HIV and tuberculosis (TB). Tuberculosis is a leading cause of death among people living with HIV; worldwide, 14 million people are co-infected with Mycobacterium tuberculosis and HIV infection . HIV infection increases the risk of reactivation latent M. tuberculosisinfection, putting HIV-positive people at greater risk of developing TB . HIV infection also increases the risk for rapid progression after primary TB M. tuberculosis acquisition or re . TB can accelerate the progression of HIV disease via immune activation and is associated with higher mortality and lower survival of HIV-positive people . The increased risk of TB CD4 as the cell count decreases; similarly, the highest mortality rates associated with tuberculosis occur in people with lower cell counts CD4 .
It is assumed that, very early in the natural history of HIV-before a significant decrease in disease-CD4 cell count occurs and the risk of TB is relatively low. So it is surprising and fascinating in this issue of The Journal of Infectious Diseases, Sonnenberg et al. , Report evidence to the contrary. In a large cohort of gold mining in South Africa, the authors found that the risk of TB has doubled in the first year of infection with HIV. Not unexpectedly, this risk increases even more in the following years.
Previous studies have suggested the possibility that the incidence of TB can increase after infection with HIV, but these studies were not able to quantify a statistically significant risk. There were several cohort characteristics analyzed by Sonnenberg et al. that allowed them to evaluate the pattern of temporal risk of TB after HIV seroconversion: the incidence of TB in the group was very high, and the cohort had a high rate of seroconversion HIV. Sonnenberg et al. were able to analyze results between 23.874 miners, including 2.737 miners with a documented HIV seroconversion. TB diagnostic capacity allowed a definitive diagnosis of TB, and the cohort had consistent access to reliable health care.
In the study, minors who were tested for HIV in sexually transmitted disease (STD) clinics during hospitalization, or as part of seroprevalence surveys, during the designated study period were eligible for enrollment. The miners were followed until they developed pulmonary TB, die, or leave the mines. HIV-negative miners were also censored for analysis in 1 year after the last HIV negative test. TB was detected during routine annual exams or patient-initiated visits to the hospital or an STD clinic. During the study period, HIV test replications were performed mainly during patient-initiated visits to the hospital or STD (or other) clinics, as well as during seroprevalence surveys.
Careful design and complex analytical study Sonnenberg et al. was necessary because of the open nature of the cohort and a desire to minimize the inclusion of TB incident among miners HIV status uncertain or unknown. The frequency and location highly variable HIV testing raises the question of whether the TB are different risks, for example, among the miners who were tested for HIV only once during an investigation seroprevalence and miners were tested repeatedly visits started in the patient to an STD clinic. Sonnenberg et al. dealt with this potential bias in sensitivity analyzes by excluding HIV testing in medical wards or TB, and the authors report a similar increase in TB incidence within the first year of seroconversion HIV.
When the TB diagnostic methods in miners were considered, which included the assessment after the presentation initiated by the patient in the hospital or medical clinics and routine annual exams, the issue of bias determination arises. Sonnenberg et al. correctly states that doctors in the gold mines are likely to have a high degree of suspicion of TB, regardless of HIV status of a miner, because of the incidence and prevalence of TB in the mines. However, HIV-positive miners may present to medical facilities more often because of the development of clinical symptoms related to the disease of HIV, thus potentially biasing for further evaluation and TB detection among HIV-positive miners. Another challenge that arises is the differing rates of friction between positive and negative HIV miners in the analysis. For HIV-negative miners with only 1 HIV test, the period of follow-up included in the analysis would be just one year, whereas, for HIV-positive miners, the follow-up period included in the analysis probably would average , longer. The short duration of follow-up for HIV-negative miners can translate into a decreased chance of detecting the development of TB, potentially reducing the estimated incidence of TB in this population. However, an average of 1,1 years of follow-up for positive and HIV-negative miners provides enough data to reveal the most fascinating discovery of the study Sonnenberg et al: doubling the incidence of TB in the first year of seroconversion HIV.
Why is the risk of developing TB increased early during the course of HIV infection? The profound immune dysregulation occurs after HIV infection may play a role. Immediately after acute HIV infection, a person goes for a period of generalized immunosuppression which is marked by decreased response to the previously exposed antigens [6,7]. This T cell dysfunction, which is not clearly correlated with CD4 cell count and can last for months  may be a mechanism that allows the progression of early after HIV infection tuberculosis. The time course of loss of response to M. tuberculosis antigens to start as soon as acute HIV infection carries a further investigation, it can shed light on this issue.
Another possible explanation for Sonnenberg et al. And the finding of an increased risk of TB early in the course of HIV infection is that the miners who developed TB during the first year of infection with HIV represent a subset of rapid progressors. In initial studies of AIDS, only 2% to 3% of patients achieved a clinical diagnosis of AIDS within 2-3 years of HIV seroconversion . However, co-infection with> 1 strain of HIV has been increasingly reported in African cohorts [9, 10], and the rapid progression rates of the disease may be much higher in these doubly infected people. In a recent study of 34 HIV-positive patients with known seroconversion dates and data on disease outcomes, 5 were found to be doubly infected (ie they or were co-infected with two virus variants at the time of seroconversion or were superinfected with one second viral variant at a later date); 5 in all these patients, the time for a cell count CD4 <200 cells / ul was <3,1 years, which is much shorter than the typical time-8 10 years . In sonnenberg et al., 138 of miners in the incident HIV-infection group (ie those who seroconverted during the study period) who developed TB during the study period, 30 developed the disease during the first year of HIV infection . It is possible that some of the miners were infected> 1 strain of HIV, resulting in a faster decrease in the cell count CD4, leading to reactivation of a latent M. tuberculosis infection.
Interestingly, the increased risk of TB early in the course of HIV infection is due to an infection or reactivation of M. tuberculosis newly acquired. To shed light on this issue, Sonnenberg et al. realizpu molecular fingerprinting of isolates available. Among seroconverters HIV, the authors found that the original TB isolates were present in 57% (8 / 14) of miners who developed TB within 2 years of HIV seroconversion, compared with 20% (3 / 15), who developed TB after . Documents isolated patients are more likely to have developed TB via reactivation, while isolates patients that are shared among a cohort are thought to have been recently infected. Any reactivation and infection with M. tuberculosis newly acquired are plausible in the context of acute immunosuppression which is associated with primary infection with HIV and HIV disease and rapidly progressive decrease in cell count CD4. The numbers of study Sonnenberg et al. are too small to draw a definite conclusion with regard to the type of TB that predominated after seroconversion HIV. It is possible that new risks of both infection and reactivation of M. tuberculosis disease is increased.
The increased risk of TB early in the course of HIV infection has several important implications for predicting the impact of HIV on the global TB epidemic. Although it is difficult to generalize the magnitude of the increased incidence found in the highly specialized population of gold miners and apply it to the rest of the developing world, it is likely that a certain significant increase in incidence occurs during the first year after HIV seroconversion . Although current models estimating the global burden of TB recognize the strong association between TB incidence and prevalence in adult HIV [11, 12], they do not represent the highest risk of TB early in the course of HIV infection. Reformulating these models in the context of these new data is likely to affect the calculated burden of TB-and not just for HIV-positive people, but for the general community as well .
The increased risk of TB early in HIV infection of course also has important implications for the prevention of tuberculosis in HIV-positive people. Potential methods include the use of antiretroviral drugs and chemoprophylaxis for latent tuberculosis infection. South African data suggest that the use of highly active antiretroviral therapy effective in reducing the incidence of tuberculosis among HIV-associated people with CD4 cell counts <350 cells / ml . If people who develop TB early during the course of HIV infection represent rapid progressors with low CD4 cell counts, then the determination of CD4 cell count may be all that is needed to identify the subset of people who are at greater risk .
Alternatively, if most people who develop TB early during the course of HIV infection have high CD4 cell counts and there are no indications for antiretroviral therapy then the treatment of latent tuberculosis infection may be the most viable path to reduce the risk of TB. Data from Uganda suggest that treatment of latent M. tuberculosis infection may provide protection against TB in HIV-positive people; the duration of protection was increased to three years by use of combined treatment regimens with rifampicin . However, the definition and implementation of optimal preventive therapy for TB in Africa is a challenging task. The optimal duration of treatment and optimal regimens are unknown and are currently under investigation. Preventive therapy programs also require the exclusion of active tuberculosis, which can be difficult in places with limited resources.
Perhaps the most immediate and universal implication of these important data Sonnenberg et al., Is the need to expand HIV testing services reliable and affordable in areas where tuberculosis is endemic. The exact identification of undiagnosed HIV is the necessary first step in the implementation of preventive measures to reduce the spread of M. tuberculosis and HIV co-infection. Timely and reliable assessment of TB in HIV-positive people is another key component that needs to be strengthened to contain the epidemic. The protest initiative that was established in three countries in Africa by the World Health Organization aims to develop a more coherent response to TB in settings where HIV prevalence is high by combining better access to high quality counseling services and rapid testing with enhanced screening for TB . Preliminary reports of these sites indicate that such collaborative efforts between HIV / AIDS and tuberculosis control programs are feasible and effective . Improving links between HIV and TB clinical services and public health will be essential to address effectively the challenges of this coepidemic.
- Padmini Srikantiah1,2,
- Edwin and Charlebois1
- Diane V. Havlir3
+ Author Affiliations
- 1 AIDS Prevention Studies Center at the University of California at San Francisco, San Francisco
- 2 Division of Infectious Diseases at the University of California at San Francisco, San Francisco
- 3 / HIV Division AIDS, San Francisco General Hospital, University of California at San Francisco, San Francisco
- Reprints or correspondence: Dr. Diane V. Havlir, HIV / AIDS Div, San Francisco General Hospital, University of California at San Francisco, 995 Potrero Ave., Bldg .. 80, 84 Ward, San Francisco, CA 94110 (dhavlir @ php.ucsf.edu).
- © 2005 by the Infectious Diseases Society of America
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