Severe bacterial infections: overlooked opportunistic diseases
Authors: Xavier Anglaret, Serge P Eholie
Journal: The Lancet HIV (2017)

In The Lancet HIV, Jemma O'Connor and colleagues1O'Connor J Vjecha MJ Phillips AN et al.Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with a CD4 cell count of more than 500 cells per μL: secondary outcome results from a randomised controlled trial.Lancet HIV. 2017; (published online Jan 4.)http://dx.doi.org/10.1016/S2352-3018(16)30216-8PubMed Google Scholar give new evidence that severe bacterial infections other than tuberculosis should be recognised as HIV-related opportunistic diseases. This study draws attention to a group of opportunistic diseases that has been somehow neglected by the HIV community. HIV activity causes progressively worsening immunosuppression. The degree of immunosuppression and the subsequent risk of opportunistic infection over time are routinely estimated with the CD4 cell count. From a clinical perspective, two main types of HIV-related opportunistic infections exist: those that almost exclusively occur in severely immunocompromised patients with low CD4 cell counts and are almost never seen in the community and those that are routinely seen in non-HIV infected people but are more frequent in HIV-infected patients (even those with high CD4 cell counts). The second type becomes increasingly common and more severe as CD4 cell counts decrease.2Hirschtick RE Glassroth J Jordan MC et al.Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group.N Engl J Med. 1995; 333: 845-851Crossref PubMed Scopus (569) Google Scholar Tuberculosis is well recognised as an infection that is both seen in the community and opportunistic, but non-tuberculous bacterial infections have received less attention from the medical community. There is good evidence that bacterial diseases are opportunistic,2Hirschtick RE Glassroth J Jordan MC et al.Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group.N Engl J Med. 1995; 333: 845-851Crossref PubMed Scopus (569) Google Scholar, 3Gilks C Ojoo S Brindle R et al.Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya.Lancet. 1996; 347: 718-723Summary PubMed Scopus (178) Google Scholar, 4Anglaret X Messou E Ouassa T et al.Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving cotrimoxazole prophylaxis in Abidjan, Cote d'Ivoire.AIDS. 2003; 17: 575-584Crossref PubMed Scopus (64) Google Scholar, 5Lucas SB Hounnou A Peacock C et al.The mortality and pathology of HIV infection in a west African city.AIDS. 1993; 7: 1569-1579Crossref PubMed Scopus (509) Google Scholar, 6Corbett EL Churchyard GJ Charalambos S et al.Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.Clin Infect Dis. 2002; 34: 1251-1258Crossref PubMed Scopus (162) Google Scholar, 7Anglaret X Chêne G Attia A et al.Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group.Lancet. 1999; 353: 1463-1468Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar but they are not viewed as a homogeneous group because of the range of pathogens and organ systems involved. Additionally, many severe bacterial diseases are not AIDS-defining, and are therefore not included in the composite morbidity outcomes of many HIV trials and not well recorded.4Anglaret X Messou E Ouassa T et al.Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving cotrimoxazole prophylaxis in Abidjan, Cote d'Ivoire.AIDS. 2003; 17: 575-584Crossref PubMed Scopus (64) Google Scholar O'Connor and colleagues report a secondary analysis of the START trial,8Lundgren JD Babiker AG Gordin F et al.Initiation of antiretroviral therapy in early asymptomatic HIV infection.N Engl J Med. 2015; 373: 795-807Crossref PubMed Scopus (2) Google Scholar in which antiretroviral therapy (ART)-naive, HIV-positive adults with CD4 count of more than 500 cells per μL were randomly assigned to either immediate ART or deferral until the count was lower than 350 cells per μL. The authors show that immediate initiation of ART not only decreased the risk of serious morbidity by 57% (the START composite primary endpoint included any serious AIDS-related event, serious non–AIDS-related event, or death from any cause), as previously published,8Lundgren JD Babiker AG Gordin F et al.Initiation of antiretroviral therapy in early asymptomatic HIV infection.N Engl J Med. 2015; 373: 795-807Crossref PubMed Scopus (2) Google Scholar but also the risk of severe bacterial infection by 61%, a secondary endpoint that combined tuberculosis and severe other bacterial diseases; and the risk of severe bacterial diseases other than tuberculosis by 59%.1O'Connor J Vjecha MJ Phillips AN et al.Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with a CD4 cell count of more than 500 cells per μL: secondary outcome results from a randomised controlled trial.Lancet HIV. 2017; (published online Jan 4.)http://dx.doi.org/10.1016/S2352-3018(16)30216-8PubMed Google Scholar Non-AIDS-defining severe bacterial infections were not included in the primary composite outcome in the START study. Another trial of early ART, Temprano ANRS 12136,9Danel C Moh R Gabillard D et al.A trial of early antiretrovirals and isoniazid preventive therapy in Africa.N Engl J Med. 2015; 373: 808-822Crossref PubMed Scopus (860) Google Scholar showed similar results. In the Temprano trial, ART-naive adults with CD4 counts of less than 800 cells per μL and no WHO criteria for starting ART were randomly assigned to immediate ART or deferral until the WHO criteria were met. Immediate initiation of ART decreased the risk of severe morbidity by 44%, a primary composite endpoint that included any invasive bacterial disease (the Temprano composite primary endpoint included AIDS-related event, non–AIDS-defining cancer, non–AIDS-defining invasive bacterial disease, or death from any cause); and the risk of non-tuberculous invasive bacterial diseases by 61%. The median baseline CD4 count of participants was 463 cells per μL in Temprano and 651 cells per μL in START.10Eholie SP Badje A Kouame GM et al.Antiretroviral treatment regardless of CD4 count: the universal answer to a contextual question.AIDS Res Ther. 2016; 13: 27Crossref PubMed Scopus (49) Google Scholar Both trials therefore show that ART has a protective effect in reducing the risk of severe bacterial infections across a wide range of high to very high CD4 cell counts. O'Connor and colleagues also show that this effect is, to a large extent, mediated by the ART-induced increase in CD4 cell count, as expected for any opportunistic infection. Therefore, these trials add to the evidence showing that severe bacterial infections are opportunistic infections in patients with HIV. The incidence of severe bacterial diseases was higher in the Temprano study, which was done solely in sub-Saharan Africa, than in the START trial, in which 45% of patients were recruited in Australia, western Europe, and the USA.8Lundgren JD Babiker AG Gordin F et al.Initiation of antiretroviral therapy in early asymptomatic HIV infection.N Engl J Med. 2015; 373: 795-807Crossref PubMed Scopus (2) Google Scholar, 9Danel C Moh R Gabillard D et al.A trial of early antiretrovirals and isoniazid preventive therapy in Africa.N Engl J Med. 2015; 373: 808-822Crossref PubMed Scopus (860) Google Scholar Whether this difference is a result of baseline difference in CD4 cell count, more systematic reporting of severe bacterial episodes that were a component of the primary endpoint in Temprano, or a true regional and economic development difference is unclear.10Eholie SP Badje A Kouame GM et al.Antiretroviral treatment regardless of CD4 count: the universal answer to a contextual question.AIDS Res Ther. 2016; 13: 27Crossref PubMed Scopus (49) Google Scholar That said, HIV-associated severe bacterial diseases are likely to be more common and more frequently lethal in low-resource settings than in high-income settings.5Lucas SB Hounnou A Peacock C et al.The mortality and pathology of HIV infection in a west African city.AIDS. 1993; 7: 1569-1579Crossref PubMed Scopus (509) Google Scholar, 6Corbett EL Churchyard GJ Charalambos S et al.Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.Clin Infect Dis. 2002; 34: 1251-1258Crossref PubMed Scopus (162) Google Scholar, 11Cox JA Lukande RL Nelson AM et al.An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda.PLoS One. 2012; 7: e33685Crossref PubMed Scopus (48) Google Scholar, 12Martinson NA Karstaedt A Venter WD et al.Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study.AIDS. 2007; 21: 2043-2050Crossref PubMed Scopus (94) Google Scholar, 13Rana FS Hawken MP Mwachari C et al.Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya.J Acquir Immune Defic Syndr. 2000; 24: 23-29Crossref PubMed Scopus (150) Google Scholar This is the reason why co-trimoxazole prophylaxis is recommended to be provided irrespective of CD4 cell count in settings with a high burden of bacterial diseases.14Suthar AB Vitoria MA Nagata JM et al.Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis.Lancet HIV. 2015; 2: e137-e150Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Given that immediate initiation of ART reduces the risk of tuberculosis and non-tuberculous bacterial infections, the WHO recommendation that ART should be initiated regardless of CD4 cell count should be taken seriously worldwide and even more seriously in settings with a high burden of tuberculosis and non-tuberculous bacterial infections. XA and SPE were the coordinating investigators of the Temprano ANRS 12136 trial. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trialImmediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. Full-Text PDF Open Access