Background
One third of the world's population is believed to be infected with Mycobacterium tuberculosis (MTb) but most infected people will never have symptoms (Dye 1999). Infection with the human immunodeficiency virus (HIV) has, however, changed the natural history of tuberculosis (TB). In HIV negative populations, only 5-10% will ever develop active tuberculosis (Enarson 1994). However, HIV positive persons who are infected with MTb have a 5-8% annual risk and a 30% lifetime risk of developing active tuberculosis (Selwyn 1989). It is estimated that close to 70% of the world's 10.7 million population dually infected with HIV and MTb live in Africa (Dye 1999). In this group, tuberculosis is the leading cause of morbidity and mortality.
The primary screening test for tuberculosis infection is the tuberculin skin test, where material derived from MTb is introduced into the skin. People infected with MTb typically have a strong reaction to this skin test, and are termed positive for the tuberculin skin test (PPD positive). They are at greater risk of subsequently developing active disease than are people who are not infected with MTb (Watkins 2000). While the risk factors for developing clinical tuberculosis are not completely understood, age (highest risk for children under 4 years old), dosage of infection, and a compromised immune system may all increase the risk of disease (Comsock 2000). Reactivation of dormant tuberculosis infection due to a weakened immune system appears to be the main mechanism for the development of HIV-related tuberculosis but HIV positive patients may also be at higher risk of acquiring new TB infection (Cobo 2002). With the progression of HIV disease, tuberculosis tends to occur at higher CD4 lymphocytes levels than other opportunistic infections (Harries 1994).
HIV infection also has implications for the diagnosis and clinical presentation of TB. The proportion of PPD negative individuals with tuberculosis infection seems to be higher in HIV positive populations than in those who are not infected with HIV (Daniel 2000). Similarly, the percentage of sputum smear negative patients with active tuberculosis is higher in HIV infected populations compared with HIV negative populations raising concerns for TB detection. Furthermore, extra-pulmonary tuberculosis is more common in patients with HIV infection than those who are not infected (Harries 1994).
It is worth noting that tuberculosis also impacts the progression and manifestation of HIV/AIDS. Active tuberculosis has been shown to accelerate the progression of HIV disease (Bocchino 2000; CDC 1998; Daniel 2000). Current research indicates that Mtb increases viral replication both in vitro and in HIV patients with active TB (Goletti 1996). In addition, it has also been shown that patients co-infected with TB and HIV are at increased risk for other opportunistic infections (Cohn 2000).
Traditional tuberculosis control strategies consist of case-finding and treatment (considered the most important short-term strategy), preventive therapy (PT), also referred to as chemoprophylaxis, and BCG vaccination of children with the knowledge that better socio-economic conditions lead to a decline in incidence of the disease. The rationale behind preventive therapy is to eradicate latent infection in PPD positive individuals before it develops into active disease.
Several placebo-controlled trials in HIV negative people infected with MTb have shown that daily isoniazid given for 6-12 months substantially reduces the subsequent risk of active tuberculosis (O'Brien 1994; Smieja 2003) However, in the context of HIV infection, a variety of factors may impact the effectiveness of TB preventive therapy. There is some evidence that absorption of antituberculous drugs may be suboptimal in patients with AIDS (Peloquin 1996). Secondly, since HIV patients may be taking anti-retroviral therapy, as well as other drugs for the treatment of AIDS-related diseases, drug interactions can arise (Kovacs 2000; Piscitelli 2001). Furthermore, adherence to treatment may be a problem in dually infected patients for reasons including serious morbidity, poly -pharmacy and adverse effects thus increasing the likelihood of multidrug-resistant tuberculosis. Assumptions about the protective potential of TB preventive therapy in HIV positive people may therefore not be warranted.
In the light of the above concerns a systematic review of the evidence concerning the effectiveness of preventive therapy for tuberculosis in HIV infected persons was conducted.
Objectives
The objective of this review was to determine the effectiveness of tuberculosis preventive therapy (PT)/chemoprophylaxis in reducing the risk of active tuberculosis and death in persons infected with HIV. The following hypotheses were proposed for testing depending on available evidence:
1. PT does not reduce the incidence of, and interval to, active tuberculosis in HIV infected persons. If PT is effective in reducing the incidence of active TB, the effect is not dependent on the following factors:
- PPD status (whether the tuberculin skin test is positive or negative)
- Degree of immunocompromise (stage of HIV disease)
- TB drug regimen including type, dosage and duration of treatment
- Time since completion of therapy
2. PT does not reduce the frequency of death in HIV infected persons.
3. PT does not slow the progression of HIV disease through reducing the incidence of AIDS and delay of time to the development of AIDS.
4. PT is not associated with an increased incidence of adverse drug reactions and different drug regimens do not have different rates of adverse reactions
Methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled studies in which individuals were randomly allocated to preventive therapy for TB and placebo, or to alternative TB preventive therapy regimens.
Preventive therapy (chemoprophylaxis) is defined as tuberculosis chemotherapy given to people at high risk of developing TB to prevent active disease.
Types of participants
Participants had to be HIV infected adults who did not have active TB currently or in the past. Participants could be of either gender and from any setting. They could be either tuberculin skin test positive (PPD - purified protein derivative) or negative. Anergic patients were considered tuberculin skin test negative.
Types of interventions
Experimental group: Any tuberculosis drug or drug combination
Control group: Inactive placebo or an alternative tuberculosis drug or drug combination
Types of outcome measures
Primary outcomes:
1. Active tuberculosis based upon microbiological diagnosis (preferably by culture), histological diagnosis, or as a defined clinical syndrome (typical symptoms, consistent and independently assessed chest X-ray, and a documented response to anti- tuberculosis treatment) (ATS 1990)
2. Interval to active tuberculosis from initiation of preventive therapy.
3. Survival including incidence of death and interval to death
Secondary outcomes:
1. Progression of HIV disease. This could include incidence of, interval to, and types of HIV-related disease, change in CD4 count or incidence of, and time to, AIDS.
2. Incidence of adverse drug reactions leading to discontinuation of treatment.
Search methods for identification of studies
We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).
We used the following terms to search for eligible randomized controlled trials or review articles: (HIV AND tuberculosis) AND (preventive therapy OR chemoprophylaxis or treatment). "Treatment" was used as a search term because we discovered some studies that discussed treatment of latent tuberculosis were indexed incorrectly under treatment. The following databases were searched through July 2002:
- The Cochrane Controlled Trials Register (CCTR)
- MEDLINE
- EMBASE
- AIDSLINE
- AIDSTRIALS
- AIDSDRUGS
We also scanned the reference lists of review articles and included studies to identify further studies. We contacted study authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this review.
Data collection and analysis
We independently applied the pre-specified study eligibility criteria to determine which studies should be included in the review. We also independently evaluated the quality of the studies according to the following predefined criteria for quality assessment
1. Generation of allocation sequence - trials were classified as
- Adequate: if appropriate methods, such as random numbers generated by computer, or throwing dice were used.
- Inadequate: if sequences such as case record number, date of birth, day, month or years of admission were used.
- Unclear: if methods were not described
2. Concealment of allocation - trials were classified as
- Adequate: if measures were used to prevent foreknowledge of assignment, such as centralized randomization or numbered, sealed, opaque envelopes.
- Inadequate: if researchers reported an approach that could not be considered adequate e.g. alternation
- Unclear: if methods were not described
3. Blinding - trials were assessed for provider, participant and assessor blinding
4. Inclusion of all randomized participants in the analysis- trials were labeled as adequate if more than 90% of the randomized participants were included.
We did not assign quality scores to studies.
We independently extracted the following information using a standardized data collection form: study setting, demographics of participants, details of interventions, methods of randomization and blinding, follow-up, degree of adherence to treatment, and outcomes. Where we were able to obtain information from either published or unpublished data, we stratified results by PPD status and HIV/AIDS status at baseline. We also extracted information on adherence to therapy.
Differences between reveiewers (SW & JV) in relation to data extraction or quality assessment were resolved by discussion and re-examination of the relevant studies.
We pooled data using relative risk (RR) with 95% confidence intervals using a fixed effects model. We tested for statistical heterogeneity of trials results at the 0.1 level. For continuous data such as time to AIDS, we used the weighted mean difference (WMD).
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
17 trials were initially included because they were thought to meet our inclusion criteria. Four of these studies were later excluded for the following reasons: one evaluated preventive therapy to reduce recurrence of TB in individuals who had previously had the disease (Fitzgerald 2000); two primarily assessed drug tolerability rather than prevention of active TB (Garcia 1993; Matteelli 1998); and one study was assumed to be non-randomized as it was described only as "prospective, comparative" (Saenghirunvatta 1996).
A further two studies are awaiting assessment for inclusion in the review because data on active TB are yet to be reported (Sanchez 2002) or the results originally presented at a conference remain unpublished and we are attempting to obtain the data (Wadhawan 1993).
The current review thus includes 11 trials with a total of 8130 randomized participants. Study size varied from 118 to 2018. The study by Whalen et al was counted as two distinct trials as randomisation was carried out separately for PPD+ persons (Whalen 1997) and those who were anergic (Whalen 1997-anergy). Follow-up data for these two trials were reported in Johnson 2001 and Johnson 2001 -anergy, respectively. Long-term follow-up results of Mwinga 1998 were in Quigley 1998. We have included one unpublished trial based using data from a conference poster presentation (Rivero 2002).
Full details of the studies included in this review are provided in the table of included studies.
Summary of included studies:
Trials were conducted in several countries: Haiti (Fitzgerald 2001; Halsey 1998; Pape 1993), Uganda (Whalen 1997), Kenya (Hawken 1997), Zambia (Mwinga 1998), Spain (Martinez 2001; Rivero 2002) and the USA (Gordin 1997). One multi-national study included participants from Mexico, USA, Haiti and Brazil (Gordin 2000).
Study participants were 13 years of age or older (mean age 32). 52% were female, with a range of 23% to 77% across trials. Mean duration of follow up ranged from 1 to 3 years.
Some reports included only individuals who were PPD+ (Gordin 2000; Halsey 1998) and others involved only those known to be anergic (Gordin 1997; Rivero 2002) Two articles included both PPD+ and anergic individuals either as separately randomized groups (Whalen 1997) or as one group with stratification by PPD status in the analysis (Martinez 2001). A further trial among PPD negative individuals did not test for anergy (Fitzgerald 2001). The remaining trials included individuals regardless of PPD status (Hawken 1997; Mwinga 1998; Pape 1993) with only two of these providing stratified data (Hawken 1997; Pape 1993)
In all, 4495 individuals were PPD+, 1932 were PPD- (of which 1640 were known to be anergic) and in 1737 individuals the PPD status was unknown.
All 11 trials evaluated isoniazid (INH) either compared with placebo (8 trials) or to a combination anti-TB regimen (3 trials): INH plus rifampicin (RIF) (3 trials), RIF plus pyrazinamide (PZA) (4 trials) and INH plus RIF plus PZA (1 trial).
Treatment dosage varied among the trials: INH 300 mg or 600mg for daily regimens; 600mg or 900 mg mg for twice weekly regimens; RIF 450 mg or 600 mg; and PZA 20 mg/kg body weight to a total of 3500 mg. Dosage frequency was daily except in two trials (Halsey 1998; Mwinga 1998) which offered treatment twice a week. The duration of INH treatment varied as follows: 12 months (Fitzgerald 2001; Gordin 2000; Martinez 2001; Pape 1993) and 6 months (Gordin 1997; Halsey 1998; Hawken 1997; Mwinga 1998; Rivero 2002; Whalen 1997). All the remaining trials evaluated short-course, rifampicin-containing combination drug therapies typically offered for 2 or 3 months.
We collected data for active TB diagnosed either by culture or other methods of diagnosis as defined by the study authors (confirmed, probable and possible). Active TB data were available for all participants. Culture -confirmed TB was available for 5039 participants (62%).
Risk of bias in included studies
Generation of randomization sequence was adequate in 5 studies and unclear in 6. Allocation concealment was adequate in 5 studies and unclear in the rest. There were only 3 trials where both sequence generation and allocation concealment were adequate.
In 3 trials both providers and participants were blinded, in 7 trials both were unblinded and in 1 blinding was unclear. Assessors were blinded in 7 trials. It should be noted that although the majority of the trials were placebo-controlled this did not ensure blinding as anti-tuberculosis drugs produce distinguishable adverse effects.
The inclusion of randomized participants was adequate in all the included trials. All randomized participants were included in analysis in 8 of the trials. The remaining studies excluded 2% (2 trials) or 4% (1 trial) of randomized participants. Participant loss to follow-up ranged from 0 to 31% (mean 11% across all studies).
(See Table of Included Studies for details of individual studies.)
Effects of interventions
ACTIVE TUBERCULOSIS
Preventive therapy (any anti-TB drug) versus placebo reduced the risk of active TB by 36% (13 trials; 5664 participants; RR 0.64, 95% CI 0.51 to 0.81). We found no statistical heterogeneity among the trials. For confirmed (culture-proven) TB, the result was similar (6 trials; 2573 participants; RR 0.73, 95% CI 0.49 to 1.08) although not statistically significant.
All drug regimens (regardless of type, frequency or duration of treatment) reduced the incidence of active TB compared with placebo:
- INH: 13 trials; RR 0.67, 95% CI 0.51 to 0.87
- INH+RIF: 2 trials; RR 0.41, 95% CI 0.21 to 0.81
- RIF+PZA: 4 trials; RR 0.54, 95% CI 0.34 to 0.86
- INH+RIF+PZA: 1 trial; RR 0.48, 95% CI 0.23 to 1.00
In trials that directly compared drug regimens we found no differences in effectiveness:
- INH vs. RIF+PZA: 6 trials; RR 1.00, 95% CI 0.73 to 1.38
- INH vs. INH+RIF: 4 trials; RR 1.05, 95% CI 0.51 to 2.17
- INH + RIF vs. RIF+PZA: 1 trial; RR 2.82, 95% CI 0.30 to 26.51
- INH vs. INH+RIF+PZA: 1 trial; RR 0.60, 95% CI 0.23 to 1.57
- INH + RIF vs. INH+RIF+PZA: 1 trial; RR 0.75, 95% CI 0.31 to 1.82
We detected no heterogeneity in the outcome across the trials.
We found no trials that compared the effects of different drug dosages, treatment frequency or duration of therapy on clinical outcomes. Current trials do not provide sufficient data to assess the impact of preventive therapy on interval to active TB.
We assessed the influence of various factors on the incidence of active TB:
PPD status
Among individuals who were tuberculin skin test positive, preventive therapy reduced the risk of active TB by 62% (4 trials; 2378 participants; RR 0.38, 95% CI 0.25 to 0.57). Although a similar trend was found for individuals with a negative tuberculin test (7 trials; 2822 participants; RR 0.83, 95% CI 0.58 to 1.18) and those with confirmed anergy (3 trials; 1554 participants; RR 0.67, 95% CI 0.36 to 1.24) these results were not statistically significant.
Stage of HIV disease at baseline
We found limited data stratified by stage of HIV/AIDS at baseline. In Gordin 1997, which compared INH to placebo, the relative risk (95% CI) for the development of confirmed TB was 3.42 ( 0.14 to 82.33) for those with AIDS and 0.32 (0.06 to 1.54) for those without AIDS; neither of these findings being statistically significant. Similarly, in Gordin 2000 comparing INH with RIF+PZA, the risk of confirmed TB was not statistically significant in subgroups defined by AIDS status: AIDS RR 0.97, 95% CI 0.28 to 3.43; no AIDS RR 1.42, 95% CI 0.74 to 2.74.
Time since treatment
We found limited information on the duration of the protective effect of preventive therapy. Mwinga 1998 provided data for a median follow-up of 1.8 years in a mixture of PPD positive and negative people found a reduction in the risk of active TB in the intervention groups versus placebo (INH: RR 0.62, 95% CI 0.39 to 0.97; RIF plus PZA: RR 0.57, 95% CI 0.35 to 0.91). In a subsequent report (Quigley 1998) presenting findings after a mean follow-up of 3 years, Kaplan Meier analysis demonstrated a diminishing effect over time. Nevertheless, compared to placebo the reported cumulative risk in the first 2.5 years remained lower for INH (RR 0.52, 95% CI 0.27 to 1.00), for RIF plus PZA (RR 0.58, 95% CI 0.30 to 1.09) and for both intervention arms combined (RR 0.55, 95% CI 0.32 to 0.93).
In another study (Whalen 1997) involving PPD positive individuals, INH (RR 0.29, 95% CI 0.12 to 0.67), INH + RIF (RR 0.36, 95% CI 0.17 to 0.77) and INH + RIF + PZA (RR 0.48, 95% CI 0.23 to 1.00) were each shown to significantly lower the risk of active TB after a mean of 15 months. This benefit remained statistically significant on long-term follow-up for the rifampicin containing regimens but not for INH alone (Johnson 2001). Based on a Cox regression analysis the adjusted relative risk at 3 years was 0.67 (95% CI 0.42 to 1.07) for INH, 0.49 (95% CI 0.29 to 0.82) for INH + RIF, and 0.41 (95% CI 0.22 to 0.76) for INH+RIF+PZA. For anergic participants the initial statistically non-signficant benefit 1 year after INH treatment (RR 0.74, 95% CI 0.30 to 0.1.79) (Whalen 1997-anergy) remained at 2 years (adjusted relative risk 0.61 (95% CI 0.32 to 1.16) (Johnson 2001 -anergy).
The long-term follow-up results for the studies mentioned above should be interpreted with caution as there was substantial loss to follow-up in all trials which may have introduced bias.
DEATH FROM ALL CAUSES
We found no evidence that preventive therapy versus placebo reduced all-cause mortality (13 trials; 5664 participants; RR 0.95, 95% CI 0.85 to 1.06). Among those who were PPD positive the trend was towards a benefit (4 trials, 2378 participants, RR 0.80, 95% CI 0.63 to 1.02), however these findings were heterogeneous (p=0.04).
The single placebo-controlled trial that assessed the effect of INH by stage of HIV/AIDS at baseline found no difference (Gordin 1997): with AIDS (RR 0.96, 95% CI 0.79 to 1.17), without AIDS (RR 1.07, 95% CI 0.84 to 1.35)
We found no differences in the effect on death by study drug with the exception of INH+RIF, which was associated with a significant reduction in the risk of death (2 trials; 1179 participants; OR 0.69, 95% CI 0.50 to 0.95). Direct comparison of different drug regimens revealed no differences.
AIDS
Based on data from two trials of an INH based regimen versus placebo (Fitzgerald 2001; Pape 1993), we found no evidence of a reduction in the incidence of AIDS (RR 0.88, 95% CI 0.60 to 1.28). However, one trial (Pape 1993) found a lower risk of AIDS in PPD + individuals (RR 0.36, 95% CI 0.15 to 0.85), but not in those with a negative skin test (RR 0.78, 95% CI 0.27 to 2.20). Pape 1993 also found a significant increase in the mean time to AIDS (in months) (WMD 7.8, 95% CI 1.71 to 13.89).
ADVERSE EVENTS
We extracted available data on adverse events deemed by the investigators as serious enough to discontinue treatment. Compared to placebo, preventive therapy led to more adverse events (5 trials; 5427 participants; RR 2.49, 95% CI 1.64 to 3.77).
The likelihood of stopping treatment due to adverse effects was higher for combination therapies than for INH monotherapy:
Compared with placebo (i.e. indirect comparison)
- INH: 5 trials; RR 1.66, 95% CI 1.09 to 2.51
- INH+RIF: 2 trials; RR 16.72, 95% CI 3.29 to 84.90
- RIF+PZA: 2 trials; RR 7.84, 95% CI 2.60 to 23.67
- INH+RIF+PZA: 1 trial; RR 26.11, 95% CI 3.56 to 191.64
Direct comparisons:
- INH vs RIF+PZA: 3 trials; RR 0.64, 95% CI 0.48 to 0.86
- INH vs INH+RIF: 3 trials; RR 0.75, 95% CI 0.46 to 1.24
- INH+RIF vs RIF+PZA: 1 trial; RR 1.08, 95% CI 0.55 to 2.13
- INH vs INH+RIF+PZA: 1 trial; RR 0.10, 95% CI 0.03 to 0.33
- INH+RIF vs INH+ RIF+PZA: 1 trial; RR 0.42, 95% CI 22 to 0.80
ADHERENCE
Less than half of the studies reported on adherence to therapy (Halsey 1998; Hawken 1997; Martinez 2001; Mwinga 1998; Whalen 1997). Differences in the definition of adherence and the level of detail varied across the studies. There is some evidence that the length of treatment may be related to degree of adherence. Halsey 1998 reported higher rates of adherence with a 2 months course of RIF+PZA as compared to 6 months of INH. Martinez 2001 reported better adherence with 3 months INH+RIF compared to 12 months INH. On the other hand, Whalen 1997, reported no difference among treatment groups which included INH for 6 months, INH+RIF for 3 months and INH+RIF+PZA for 3 months. Hawken 1997, a placebo-controlled trial of INH for 6 months, found no difference in adherence rates between the two study arms. We did not have sufficient data to assess adherence as an effect modifier in the studies included in the review.
Discussion
In countries where antiretroviral treatment is not yet widely available, measures to control opportunistic infections, including tuberculosis, are especially important. This systematic review which updates a previous Cochrane review (Wilkinson 1998) confirms that chemoprophylaxis with anti-tuberculosis drugs reduces the risk of clinical tuberculosis in HIV infected populations. For INH monotherapy the short-term reduction in the relative risk compared to placebo of one-third is only half of that in people who are HIV-negative (Smieja 2003), the absolute risk reduction (ARR) for active tuberculosis is greater (2% vs 1%). In HIV positive and negative individuals the pooled number-needed-to-treat (NNT) to prevent one case of TB is therefore 50 and 100, respectively. However, among people infected with HIV who have a positive tuberculin test, chemoprophylaxis appears to be substantially more beneficial (INH: ARR 5%, NNT 20). The combined NNT should, however, be interpreted with caution as NNTs in individual trials will be influenced by a number of factors, including baseline incidence rates, misclassification of cases and duration of follow-up.
How long the initial benefit conferred by anti-tuberculosis drugs on the incidence of active tuberculosis persists is not known with certainty. Based on two studies with limited follow-up, it seems that the initial protection conferred by chemoprophylaxis may diminish over time. Whether HIV positive individuals living in areas of high TB prevalence should receive repeated courses of preventive treatment or even remain on life-long treatment cannot be answered from currently available research.
Although there appears to be no difference in benefit from alternative anti-tuberculosis drugs/drug combinations for the outcomes examined, current trials do not provide sufficient data on drug resistance and adherence to treatment which, along with information on cost, would be important for choosing a particular drug regimen. Adverse effects leading to discontinuation of treatment were more common in trials using multi-drug combination therapy as opposed to INH alone.
The finding from one study that preventive therapy may reduce the incidence of AIDS and time to full-blown disease is plausible (Pape 1993). It is known that mycobacterium tuberculosis can activate HIV-infected CD4 lymphocytes and this may lead to progression from HIV infection to clinical AIDS (Daniel 2000). This observation, however, awaits confirmation in further trials.
Currently available trials do not provide sufficient data to draw firm conclusions about the value of preventive therapy for improving survival in persons infected with HIV. It was also not possible to determine whether the effects of treatment are influenced by the stage of HIV disease at baseline.
Potential limitations of the review
We used a comprehensive search strategy to identify studies and contacted authors for clarification of reported findings or for additional data. A funnel plot of the treatment effects with active TB as the outcome was symmetrical suggesting a reduced likelihood of publication bias. We also used methods to minimize systematic error in the extraction of data and assessment of methodological quality of included studies. Trials seemed to be of good quality although key components of quality, such as allocation concealment, were not reported in many of the studies. Although the trial characteristics varied it is reassuring that we found no statistical heterogeneity for the primary outcomes assessed in this review. Finally, as most of the trials were conducted in developing countries, the results of this review are likely to be applicable to the situations where the burden of tuberculosis is high and preventive therapy is most needed.
Authors' conclusions
Implications for practice Current guidelines recommending preventive therapy in HIV infected individuals who are tuberculin skin test positive are supported by the results of this review (CDC 1998; WHO 1998). However, in developing countries, especially in Africa, where the rates of both tuberculosis and HIV infection are high, logistical and financial barriers to wide-scale use of chemoprophylaxis may be substantial. Care should be taken that a programme of preventive therapy does not divert resources from treating active tuberculosis or from offering antiretroviral therapy to the large numbers of people who may need HIV/AIDS treatment. In addition, poor adherence and drug resistant TB disease potentially associated with the use of long courses of isoniazid monotherapy should be considered. Multi-drug regimens containing rifampicin may help overcome these problems, but may be unaffordable in low- and middle-income countries. Policy makers should take all these factors into consideration when designing broad public health interventions. |
Implications for research Trials assessing the long-term effects of anti-tuberculosis chemoprophylaxis are needed to more adequately assess the duration of benefit in various settings. These trials should be large enough to assess overall mortality as an endpoint and should also assess the impact of preventive treatment on progression of HIV disease. Whether the level of immunocompromise in HIV positive individuals influences the efficacy of preventive therapy is still not known and this question warrants further study. The cost-effectiveness of anti-tuberculosis drugs compared to highly active antiretroviral therapy for preventing active tuberculosis should also be evaluated. |
Acknowledgements
We wish to express thanks to Heiner Bucher, Joan Cayla, Richard Chassion, Fred Gordin, Jo Haviland, Mark Hawken, Alberto Mattelli, John Matts, Piero Olliaro, Ratana Panpanich, and Maria Quigley for providing us with clarifications and unpublished data.
We are also grateful to Gary Maartens for valuable comments on earlier drafts and David Wilkinson who prepared the original review. Finally, we wish to thank the Cochrane Infectious Diseases Group who transferred this review to the HIV/AIDS Group for updating.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
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What's new
Last assessed as up-to-date: 25 November 2003.
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History
Review first published: Issue 2, 1996
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Contributions of authors
SW and JV both contributed to the update of this review
Declarations of interest
We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).
Sources of support
Internal sources
- Global Health Council, USA.
External sources
- World Health Organisation, Switzerland.
Index terms
Medical Subject Headings (MeSH)
AIDS-Related Opportunistic Infections [prevention & control]; Antitubercular Agents [*therapeutic use]; HIV Infections [*complications]; Isoniazid [therapeutic use]; Randomized Controlled Trials as Topic; Tuberculosis, Pulmonary [*prevention & control]
MeSH check words
Adult; Humans