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Untreated HIV: harmful even at high CD4 cell counts -
Editorial - 'When To Begin HAART'
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The Lancet, Early Online Publication, 16 July 2010
Ingrid V Bassett aEmail Address, Paul E Sax b
a Divisions of Infectious Disease and General Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
b Division of Infectious Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
"several important findings.....mortality remains higher for the untreated HIV-infected population with a CD4 count of more than 350 cells per ±L than in the general population, with substantial differences between risk groups......Higher CD4 cell counts were associated with a lower risk of death: counts of 500-699 cells per ±L had an adjusted rate ratio of 0·77 (0·61-0·95), and counts greater than 700 cells per ±L had a rate ratio of 0·66 (0·52-0·85), compared with counts of 350-499 cells per ±L......Lodwick and colleagues have amassed a very large database of patients with CD4 cell counts more than 350 cells per ±L, and more than 60% of patients had a CD4 cell count above 500 cells per ±L. A consistent finding of today's study, and other similar studies, is that deaths result from diseases not encompassed by the clinical definition of AIDS-cardiovascular, renal, and hepatic disease-and non-AIDS-defining malignant diseases......A proposed mechanism for how HIV infection might increase the risk of these non-AIDS events includes the harmful effects of chronic inflammation, immune activation, and subclinical immunodeficiency.9 Irrespective of the cause, these non-AIDS events are increasingly important in treated and untreated populations; one study showed that patients with high CD4 cell counts had a greater mortality after serious non-AIDS events than after AIDS-related clinical events.10, 11.....With the results of the INSIGHT START trial15 probably years away, clinicians must aggressively screen, prevent, and treat risk factors for chronic diseases that seem to account for the residual excess mortality in early HIV-infection. Factors include tobacco use, injecting drug use, hyperlipidaemia, hypertension, diabetes, obesity, and viral hepatitis. Even for those with relative immune competence, HIV infection remains a foe with many faces."
HIV-infected individuals with low CD4 cell counts and advanced immune suppression have a high mortality rate. But what is the effect of untreated HIV infection in individuals at an earlier stage of disease who have CD4 cell counts that put them at a lower risk for AIDS-related complications? In The Lancet today, Rebecca Lodwick and colleagues1 examine whether people with higher CD4 counts, who have not received antiretroviral therapy, have higher mortality than the general population. These investigators combined data from 23 cohorts and collaborations (18 European and five North American), and focus on 40 830 adults with at least one CD4 cell count greater than 350 cells per ±L, and up to 1 year of follow-up. They compared death rates adjusted for age, sex, and country in the HIV-infected sample with that in the general population with standardised mortality ratios, stratified by risk groups. They also estimated the difference in risk of death at high CD4 count strata compared with a stratum of 350-499 cells per ±L.
Lodwick and colleagues' study has several important findings. The first is that mortality remains higher for the untreated HIV-infected population with a CD4 count of more than 350 cells per ±L than in the general population, with substantial differences between risk groups. Standardised mortality ratios were lowest for homosexual men (1·30, 95% CI 1·06-1·58), and higher for heterosexual individuals (2·94, 2·28-3·73) and injecting drug users (9·37, 8·13-10·75). Furthermore, adjusted rate ratios indicate a mortality gradient across strata of CD4 cell counts. Higher CD4 cell counts were associated with a lower risk of death: counts of 500-699 cells per ±L had an adjusted rate ratio of 0·77 (0·61-0·95), and counts greater than 700 cells per ±L had a rate ratio of 0·66 (0·52-0·85), compared with counts of 350-499 cells per ±L. These findings were unchanged across several sensitivity analyses, and were confirmed in a subanalysis with adjustments for hepatitis C infection and smoking.
Particular strengths of this study are its large sample size, the inclusion of cohorts across several countries, and the fact that the population was limited to individuals who have never started therapy.2-5 By restricting the cohort to people not receiving treatment, Lodwick and colleagues isolated the effect of HIV infection itself from the benefits and accompanying toxic effects of antiretrovirals. The standardised mortality ratios for even the lower-risk HIV-infected groups were similar to the increased risk of death attributable to other chronic disorders, such as obesity and type 2 diabetes.6-8
Lodwick and colleagues have amassed a very large database of patients with CD4 cell counts more than 350 cells per ±L, and more than 60% of patients had a CD4 cell count above 500 cells per ±L. A consistent finding of today's study, and other similar studies, is that deaths result from diseases not encompassed by the clinical definition of AIDS-cardiovascular, renal, and hepatic disease-and non-AIDS-defining malignant diseases.
A proposed mechanism for how HIV infection might increase the risk of these non-AIDS events includes the harmful effects of chronic inflammation, immune activation, and subclinical immunodeficiency.9 Irrespective of the cause, these non-AIDS events are increasingly important in treated and untreated populations; one study showed that patients with high CD4 cell counts had a greater mortality after serious non-AIDS events than after AIDS-related clinical events.10, 11
As Lodwick and co-workers note, the large difference in mortality based on risk groups suggests that there is residual confounding by socioeconomic, health-seeking behaviour, and other unmeasured factors in patients identified early in the course of HIV infection. Although this study included mostly men (74% of the cohort), and is limited to health care in the European and North American settings, the population is representative of the epidemic in these regions. As a result, today's study adds to the observational evidence of persistently increased mortality at high CD4 cell counts. Would a similar finding be observed in resource-limited settings? Arguably the effect of untreated HIV infection on mortality in individuals with higher CD4 cell counts would be even greater, in view of the higher prevalence of virulent infectious diseases, such as tuberculosis and invasive bacterial infections.12
Lodwick and colleagues' study is one of the largest observational studies to analyse increased mortality in less-advanced HIV infection. Whether starting antiretrovirals at higher CD4 cell counts than are recommended in US and European guidelines reduces this risk remains unknown; at least one trial comparing immediate versus deferred antiretrovirals in these patients is in progress.13-15
With the results of the INSIGHT START trial15 probably years away, clinicians must aggressively screen, prevent, and treat risk factors for chronic diseases that seem to account for the residual excess mortality in early HIV-infection. Factors include tobacco use, injecting drug use, hyperlipidaemia, hypertension, diabetes, obesity, and viral hepatitis. Even for those with relative immune competence, HIV infection remains a foe with many faces.
IVB declares that she has no conflicts of interest. PES is a consultant or scientific adviser for Abbott, Bristol-Myers Squibb, Gilead, Merck, Tibotec, and ViiV, and is receiving research grants for clinical trials from Gilead, Merck, and Tibotec.
References
1 Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per ±L in Europe and North America: a pooled cohort observational study. Lancet 201010.1016/S0140-6736(10)60932-4. published online July 16. PubMed
2 Bhaskaran K, Hamouda O, Sannes M, et alfor the CASCADE Collaboration. Changes in the risk of death after HIV seroconversion compared with mortality in the general population. JAMA 2008; 300: 51-59. CrossRef | PubMed
3 Lewden C, Chene G, Morlat P, et al. Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) CO8 APROCO-COPILOTE and CO3 AQUITAINE Study Group. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46: 72-77. PubMed
4 Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007; 146: 87-95. PubMed
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7 Gnavi R, Petrelli A, Demaria M, Spadea T, Carta Q, Costa G. Mortality and educational level among diabetic and non-diabetic population in the Turin Longitudinal Study: a 9-year follow-up. Int J Epidemiol 2004; 33: 864-871. CrossRef | PubMed
8 Katzmarzyk PT, Janssen I, Ardern CI. Physical inactivity, excess adiposity and premature mortality. Obes Rev 2003; 4: 257-290. CrossRef | PubMed
9 Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009; 338: a3172. PubMed
10 The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008; 197: 1133-1144. CrossRef | PubMed
11 Neuhaus J, Angus B, Kowalska JD, et al. Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV. AIDS 2010; 24: 697-706. CrossRef | PubMed
12 Moh R, Danel C, Messou E, et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa. AIDS 2007; 21: 2483-2491. CrossRef | PubMed
13 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. (accessed July 7, 2010).
14 Clumeck N, Pozniak A, Raffi Fthe EACS Executive Committee. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults. HIV Med 2008; 9: 65-71. CrossRef | PubMed
15 INSIGHT. Strategic Timing of Antiretroviral Therapy (START). http://insight.ccbr.umn.edu/start. (accessed June 9, 2010).
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