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HIV as an inflammatory disease.

'HIV disease is characterised by a mixture of immune suppression and immune activation. So far we have focused only on fixing the suppressive side of the disease.'

For many years the focus of HIV management has rightly moved from opportunistic infection treatment and prevention to control of viraemia, as advances in new drug development and clinical trials have brought a number of new drugs, and new drug classes, to the clinic. While our patients are predominantly controlling HIV replication and have heartening recoveries in CD4 cell counts, we might think that the battle is over. However, we have succeeded in only one part of a dual-faceted disease.

Our immune response to pathogens represents a two-edged sword in many respects; able to generate vigorous responses to protect us from infections, but in doing so, can also damage our body. With regard to HIV infection, the immune response has always been considered suboptimal as the majority of people are unable to clear the virus and suffer from progressive declines in CD4 cell numbers. It was recognised from the earliest reports of AIDS that the CD4 cell depletion was also accompanied by a CD8 cell increase (with a resulting inversion of the normal CD4/CD8 ratio). We have tended to ignore this CD8 evaluation, as the immune suppression is the key process that affects patient mortality. Once viral load testing became routine, the efforts of most clinicians have focused on using combination antiretroviral therapy (ART) to control replication. This we can now do effectively; with 94% of ART-treated patients at our clinic having a viral load below 50 copies/ml.

With cessation of HIV-induced immune deficiency, more attention can now be focused on the long-term effects of chronic immune stimulation. The articles in this issue focus on some of these aspects.


Perhaps the most immediate concern with chronic inflammation is its effect on accelerating cardiovascular disease (CVD). As mortality associated with opportunistic infections has virtually disappeared, we are now facing patients whose HIV is suppressed, whose CD4 cell counts are normal or near normal; but yet who are ageing and accumulating cardiovascular risk factors. The majority of the patients seen at this clinic are males over 45, 44% of whom are smokers, with antiretroviral therapy-related increases in cholesterol, declining renal function and increasing blood pressure. In addition, many have evidence of chronic inflammation, as evidenced by high CRP levels. As noted by Chan and colleagues in their extensive review of this area, inflammation is bad for the cardiovascular system. The results of a recent cross-sectional study [1] suggest that the impact of HIV infection on thickening of carotid arteries is of the same magnitude as being diabetic or a smoker. Similar findings are reported by Hsue et al. [2], who found that narrower carotid arteries were seen in HIV-infected patients compared with non-HIV-infected patients, even when viral loads were very low (either through the strength of the immune response or treatment). These data suggest that the inflammation associated with HIV disease accelerates cardiovascular disease. As inflammation is not considered in most of the traditional CVD risk calculators, for example the Framingham score, the true risk for HIV patients is probably significantly underestimated, as suggested by a recent exploratory analysis within the DAD cohort [3].

Inflammatory markers are elevated with HIV infection and reduce as viraemia falls. Treatment interruption allows reactivation of virus, increasing these markers, and presumably accounts for the increased risk of thrombotic events seen in the SMART study [4]. Although certain drugs, for example indinavir, lopinavir, abacavir and possibly didanosine, are associated with an increased risk of cardiovascular events, the event rates are still lower than that seen in untreated patients and should not be a valid reason for deferring ART.

However, the relative impact of individual antiretroviral drugs in exacerbating CVD is unclear. Although DAD cohort data suggested an association between abacavir and myocardial infarction, with an increase in inflammatory markers postulated from the SMART dataset, randomised trials have failed to show this effect. In fact, the HEAT study, which compared Kivexa and Truvada found no deleterious effects from abacavir in a range of factors: highly specific C-reactive protein (hsCRP), interleukin-6 (IL-6) and soluble vascular cellular adhesion molecule-1 (sVCAM-1). Indeed, all of these markers improved with control of viraemia [5]. It is feasible that some channelling has occurred towards using more potent (protease inhibitors) or less mitochondrially toxic drugs (abacavir) in more heavily treated patients, thus associating these drugs with the worst CVD outcomes.

In a more recent study, carotid intima thickness was also found to be significantly associated with increased levels of CD8 activation, as expressed by elevated CD38+ subsets [6].

So, simply put, HIV seems to induce inflammation, thus increasing levels of pro-inflammatory cytokines circulating around the body, which in turn increase the risk of platelet adhesion and acute myocardial infarction. It is intriguing to see the impact of statins in reducing CVD mortality in the general population, even those with apparently acceptable cholesterol levels but who have increased levels of inflammation (as measured by hsCRP). Treating HIV reduces these inflammatory markers; however, individual drugs, particularly those that increase lipids, accelerate cholesterol deposition in arteries. At present, the role of more traditional anti-inflammatory drugs in this equation is not so clearly defined. Unfortunately, among HIV specialists currently, there seems to be a great enthusiasm for hunting for evidence to blame certain drugs, and this risks detracting from the greater evidence that untreated HIV is far more dangerous to the cardiovascular system than treated disease.


Chronic immune activation is not good for the immune system itself, let alone the rest of the body. What are the effects of years of lymphocyte stimulation, excessive cytokine levels, continual lymphocyte replication rates, telomere erosion and apoptosis on lymphoid tissue? It was recognised early in the course of HIV disease that lymphoid scarring and accelerated immunological senescence occurred with long-term untreated disease. A recent intriguing finding [7] was of collagen replacing normal lymph node architecture in patients who were unable to adequately regenerate CD4 cells despite good viral suppression. This suggests that progressive fibrosis from ongoing replication and inflammation will impair CD4 cell recovery in some treated patients. How many patients might be affected by this phenomenon as they age is unknown, but a cause for concern.

In addition to the detrimental effects of chronic inflammation on the cardiovascular and lymphoid systems, recent data from the SMART database also suggests that inflammation accelerates the development of opportunistic infections in HIV-infected patients. Patients in this study who had higher levels of IL-6 and hsCRP were more likely to develop an opportunistic infection compared to matched controls [4]. This suggests that the CD8 hyperactivation associated with ongoing HIV infection is impairing CD4 function. This is yet another argument in favour of ART initiation.

Why is the immune system chronically stimulated despite apparent suppression of viral replication? The most obvious answer is that ongoing release of HIV antigens from the latent pool is sufficient to maintain lymphoid activation. Although antiretroviral drugs can prevent new rounds of replication, they cannot prevent release of virus from cells infected in the past. Recent intensification studies with raltegravir added to apparently effective therapy, have failed to make an impact on this background viral release, when monitoring with ultra-sensitive viral load assays.

Another theory postulated by Dr Byakwaga and colleagues is that early in the course of HIV infection, lymphocyte dysregulation in the gut allows bacterial translocation to occur, and this acts as an ongoing stimulus for immune activation.


HIV, and the immune responses it generates, causes long-term deleterious effects. Controlling viral replication is clearly better than leaving it unchecked, not solely to avoid immune suppression and opportunistic infections, but also to reduce the effects of chronic immune activation. It is this control of immune activation that presents a compelling argument for early initiation of therapy, perhaps even as soon as HIV is diagnosed, regardless of surrogate markers of immune deficiency. Future research should focus on identifying markers for those at greatest risk of immune activation disease and incorporating these markers into management guidelines.


[1.] Grunfeld C, Delaney JA, Wanke C et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS, 2009, 23, 1841-1849.

[2.] Hsue PY, Hunt PW, Schnell A et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS, 2009, 23, 1059-1067.

[3.] Law MG, Friis-Moller N, El-Sadr WM et al. D:A:D Study Group. The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med, 2006, 7, 218-230.

[4.] Rodger AJ, Fox Z, Lundgren JD et al. INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis, 2009, 200, 973-983.

[5.] Smith KY, Patel P, Fine D et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS, 2009, 23, 1547-1556.

[6.] Tincati C, Bellistri GM, Casana M et al. CD8+ hyperactivation and senescence correlate with early carotid intima-media thickness in HIV+ patients with no cardiovascular disease. J Acquir Immune Defic Syndr, 2009, 51, 642-644.

[7.] Nies-Kraske E, Schacker TW, Condoluci D et al. Evaluation of the pathogenesis of decreasing CD4+ T cell counts in human immunodeficiency virus type 1-infected patients receiving successfully suppressive antiretroviral therapy. J Infect Dis, 2009, 199, 1648.

Correspondence to: Don Smith, Director of Clinical Services Albion Street Centre, Sydney, Australia Email:

Don Smith

Director of Clinical Services, Albion Street Centre, Sydney, Australia
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Article Details
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Title Annotation:EDITORIAL
Author:Smith, Don
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:8AUST
Date:Nov 1, 2009
Previous Article:16th Conference on retroviruses and opportunistic infections, Montreal, Canada, 8-11 February 2009.
Next Article:Immune activation and the pathogenesis of HIV disease: implications for therapy.

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