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Is smoking tobacco an independent risk factor for HIV infection and progression to AIDS? A systemic review
  1. A S Furber1,
  2. R Maheswaran2,
  3. J N Newell3,
  4. C Carroll4
  1. 1South East Sheffield Primary Care Trust, 9 Orgreave Road, Sheffield S13 9LQ, UK
  2. 2Public Health GIS Unit, School of Health and Related Research, University of Sheffield, Regents Court, 30 Regent Street, Sheffield S1 4DA, UK
  3. 3Institute of Health Sciences and Public Health Research, 71-75 Clarendon Road, University of Leeds, Leeds LS2 9PL, UK
  4. 4School of Health and Related Research, University of Sheffield, Regents Court, 30 Regent Street, Sheffield S1 4DA, UK
  1. Correspondence to:
 Dr Andrew Furber
 South East Sheffield Primary Care Trust, 9 Orgreave Road, Sheffield S13 9LQ, UK; a.furber{at}sheffield.ac.uk

Abstract

Objectives: To systematically review the evidence of the relation between smoking tobacco and HIV seroconversion and progression to AIDS.

Methods: A systematic review was undertaken of studies to look at tobacco smoking as a risk factor for either HIV seroconversion or progression to AIDS.

Results: Six studies were identified with HIV seroconversion as an outcome measure. Five of these indicated that smoking tobacco was an independent risk factor after adjusting for important confounders with adjusted odds ratios ranging from 1.6 to 3.5. 10 studies were identified using progression to AIDS as an end point of which nine found no relation with tobacco smoking.

Conclusions: Tobacco smoking may be an independent risk factor for HIV infection although residual confounding is another possible explanation. Smoking did not appear to be related to progression to AIDS although this finding may not be true in developing countries or with the longer life expectancies seen with highly active antiretroviral therapy.

  • CI, confidence interval
  • DALYs, disability adjusted life years
  • HAART, highly active antiretroviral therapy
  • OR, odds ratio
  • PCP, Pneumocystis carinii pneumonia
  • RH, relative hazard
  • RR, relative risk
  • HIV
  • AIDS
  • tobacco
  • seroconversion
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Tobacco and HIV/AIDS represent the only two major causes of death globally that continue to grow.1 The intersection of these two epidemics represents an area of growing clinical and public health importance.

The global HIV epidemic largely affects developing countries. Of the world’s 39.4 million people living with HIV/AIDS, 64% are in sub-Saharan Africa and 18% are from south and South East Asia.2 Global tobacco related deaths are estimated to increase from 3.0 million in 1990 to 8.4 million in 2020. Tobacco use is projected to account for 9.0% of global disability adjusted life years (DALYs) by 2020, which would make it the world’s single largest health problem.3

There is a growing recognition that cigarette smoking increases the risk of infection,4 including sexually transmitted infections.5 The possible mechanisms for this include structural modification in the lung and immunological changes. The latter include both cellular and humoral alteration such as decreasing the level of circulating immunoglobulins, the depression of antibody responses, a decrease in CD4 lymphocyte counts, an increase in CD8 lymphocyte counts, depressed phagocyte activity, and decreased release of proinflammatory cytokines.4 However it often remains unclear how these changes relate to clinical outcomes. The aim of this study was to systematically review the evidence on whether smoking tobacco is an independent risk factor for two clinically important outcomes for HIV infection—namely, seroconversion and progression to AIDS.

METHODS

Search strategy

In February 2005, we searched 13 bibliographic databases (Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, Database of Abstracts of Reviews of Effects (DARE), Embase, Health Management Information Consortium (HMIC), Medline, NHS HTA, PreMedline, PsychINFO, Science and Social Science Citation Indexes, the Current Controlled Trials database, and the UK National Research Register). We also conducted a search of abstract databases from three international AIDS conferences (2000, 2002, 2004), the World Health Organization website (www.who.int), and the Google search engine. Further unpublished reports were sought by contacting key experts and by a call for information through an email discussion group for tobacco control (Globalink). The reference lists from full papers were also checked. The searches were not limited by date.

Searches were performed using both free text and keywords. We used the following keywords and truncated free text terms: HIV, human immunodeficiency virus, human immune deficiency virus, HIV Infectio*, human immunodeficiency virus infection*, AIDS, acquired immunodeficiency syndrome, acquired immune deficiency syndrome, tobacco, smok*, nicotin*, cigarette smoking, and cigar*.

Inclusion criteria are listed in table 1. Exclusion criteria were studies concerned with paediatric HIV (for example, mother to child transmission), study participants who already had AIDS, and non-English language publications.

Table 1

 Inclusion criteria

Analysis

Data were extracted independently by two researchers (AF and RM) using a standard proforma covering year of publication, setting/country, sample size, population characteristics, study design, outcome measures, findings, and study limitations. We extracted both adjusted and crude results where available. Where no effect size had been estimated we reviewed the available data to see if this could be calculated. We assessed study quality using the Newcastle-Ottawa Scale6 as recommended by the Cochrane Collaborative Review Group on HIV Infection and AIDS.7 Meta-analysis was not undertaken as the studies identified used such a variety of approaches that it was considered that pooled results would be potentially misleading.

As the study represents secondary research, we did not seek ethics committee approval.

RESULTS

Numbers of studies

We identified 3718 studies from the searches. After removing duplicates using Reference Manager software this number fell to 2808. The titles of these papers were reviewed to remove obviously irrelevant studies producing 121 references for which abstracts were read. From these, 49 papers were obtained and read in full; 15 papers met the inclusion criteria and are summarised in tables 2 and 3. Nine of these studies used progression to AIDS as an outcome measure, five used HIV seroconversion, and one used both.

Table 2

 Papers using HIV seroconversion as the outcome measure ranked by study quality (best quality study first)

Table 3

 Papers using progression to AIDS as the outcome measure ranked by study quality (best quality study first)

Smoking tobacco as an independent risk factor for HIV infection

Six papers assessed whether smoking was associated with an increased risk of acquiring HIV infection (table 2). Of these five found that it was and one that it was not. The study that did not find an association17 produced an adjusted odds ratio of 1.22 in favour of an association but the 95% confidence interval (0.99 to 1.50) was consistent with no association. The other studies produced adjusted odds ratios ranging from 1.6 to 3.5. Crude odds ratios where provided were all larger than the adjusted ratios and ranged from 2.4 to 4.7. One paper18 did not provide an estimate of effect size and it was not possible to calculate one from the data provided.

Smoking tobacco as an independent risk factor for progression to AIDS

Ten papers assessed whether smoking was associated with more rapid progression to AIDS (table 3). Of these nine found no association. The study that did find an association was one of the poorer quality studies.30 Although not formally within the terms of this review, it is worth noting that two studies did note an association between smoking and the development of bacterial pneumonia.23,25 One of these25 also noted an association between smoking and increased risk of developing AIDS related dementia but a protective effect against Kaposi’s sarcoma.

DISCUSSION

The studies identified in this systematic review indicate that while smoking might be independently associated with acquiring HIV infection, it does not appear to be related to progression to AIDS.

The consistency of the findings is striking and represents a major strength of this review. While the studies vary in quality, they include reports of high quality investigations using large sample sizes. However the methodology necessarily used (epidemiological, observational studies) is unable to demonstrate causal relations and is prone to confounding. Most of the studies assessing the association between smoking and HIV seroconversion were cross sectional. The only truly prospective study17 found no association. In contrast, all of the studies investigating the association between progression to AIDS and smoking were cohort studies and eight out of the 10 were prospective. Confounding is more likely to occur when exposure is measured at the same time as outcome (as in cross sectional studies) and this may well explain the paradoxical finding of an association between smoking and HIV seroconversion but not with progression to AIDS.8,9

The measurement of the relevant risk factors including sexual behaviour and smoking status is difficult: these were mostly assessed from self reported data. Current smoking status is possible to verify biochemically but none of the studies did this. While the fundamental potential risk factor is past rather than current smoking status, validation of current smoking status might have gone some way to confirming self reported data. The studies included in this review classified ex-smokers as non-smokers in their analysis. This could cause possible misclassification bias. The effect of this would be to reduce any association between smoking and HIV seroconversion and progression to AIDS. Although attempts were made to identify unpublished studies, publication bias cannot be ruled out. Investigators who did not find an association between smoking and HIV seroconversion may not have tried or have been able to publish their findings. However publication bias is unlikely to be a factor for progression to AIDS, given the lack of association with smoking in published studies.

However, the consistent finding of an association between smoking and increased risk of becoming HIV seropositive could be a real effect. There is a theoretical basis for smoking being related to an increased risk of infection generally and an observed association in other infections, including sexually transmitted infections.4,5 The size of the effect observed (adjusted odds ratios ranging from 1.6 to 3.5) in the studies would indicate a magnitude of public health importance. Likewise, the consistent finding of no association between smoking and progression to AIDS could represent the true picture. Most of the studies were done before the widespread use of antiretroviral therapy and were conducted over a relatively short period of time in industrialised countries. In these circumstances it may be the case that smoking contributes little to the risk of developing AIDS. This may be because the immune mechanisms that smoking affects are less relevant in progression to AIDS than in acquiring the infection in the first place.

Further research is also needed to investigate whether the association between smoking and HIV seroconversion is related to residual confounding. Such research would need to prospectively record more accurately HIV risk behaviours including sexual intercourse and injecting drug use. Given the sensitivity of these issues and the difficulty of getting accurate self reported information, it may be preferable to “piggyback” studies on smoking and HIV onto ongoing cohort studies in high prevalence countries. The fact that all the studies that examined progression to AIDS were set in developed countries is an important limitation. Given that highly active antiretroviral therapy (HAART) has dramatically increased life expectancy for people with HIV, it may now be the case that smoking causes intercurrent illness, which could contribute to general debilitation and progression to AIDS. In particular, in developing countries where bacterial pneumonia might be less well treated and tuberculosis is more prevalent,10 smoking might be an important risk factor. Data from the United States suggest that smokers taking HAART had more inter-current, non-AIDS defining illnesses than non-smokers.11 The relation between long term treatment, dyslipidaemia, and the development of cardiovascular disease will also be of importance when considering the effects of smoking.12

Although most studies identified in this review were set in developed countries, future research must examine the effect of smoking of people living with HIV in developing countries where the AIDS epidemic has the greatest impact. Although we already know tobacco control and smoking cessation are important public health measures, such research might add evidence to inform decisions at population and individual levels. The public health message on smoking remains clear—tobacco is not good for health. Smoking prevalence is high among groups who are also vulnerable to HIV infection, including sex workers and men who have sex with men. In developing countries these groups are especially marginalised and providing any sort of support, let alone smoking cessation services, is difficult. Research is required into the best approaches for these groups.13

Key messages

  • Smoking tobacco is known to be associated with immunological changes and an increased risk for certain infections

  • Studies identified in this systematic review indicated that smoking was associated with an increased risk of HIV seroconversion but no increased risk of progressing to AIDS

  • Tobacco control and smoking cessation as well as being essential public health measures, may also contribute to the effectiveness of HIV/AIDS programmes

  • Further research is required to understand the effect of smoking since the introduction of HAART and on the health of people living with HIV in developing countries

Acknowledgments

The authors wish to thank Aileen McIntosh for advice on assessing the quality of the papers and to the editors and anonymous reviewers for constructive comments.

CONTRIBUTORS
 The study was conceived by AF and the protocol was developed by all the authors; CC developed and performed the literature searches; AF and RM extracted the data; AF wrote the first draft with all authors contributing to later drafts; AF is the guarantor.

REFERENCES

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Footnotes

  • Published Online First 21 August 2006

  • Funded by the University of Sheffield Academic Development Committee funds. The views expressed are those of the authors and not necessarily their employing or funding organisations.

  • Competing interests: none

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