Abstract
Death rates from AIDS-related events in HIV-positive individuals have declined in the era of highly active antiretroviral therapy (HAART). It has also been shown that deaths from non-AIDS events have declined in this cohort since the advent of HAART. We review these data, as well as discussing some of the possible effects HAART might have on non-AIDS diagnoses and deaths in HIV-positive individuals with successfully treated HIV.
Keywords
INTRODUCTION
Death rates from AIDS-related events in HIV-positive individuals have declined in the era of highly active antiretroviral therapy (HAART). 1 It has also been shown that deaths from non-AIDS events have declined in this cohort since the advent of HAART (Mocroft A, unpublished data). We review these data, and discuss some of the possible effects HAART might have on non-AIDS diagnoses and deaths in HIV-positive individuals with successfully treated HIV.
DISCUSSION
Successful antiretroviral therapy (ART) implies an adherent patient experiencing minimal side-effects, who has achieved viral suppression of HIV in plasma (<50 copies/mL) and immunological restoration with a CD4 count >200 cells/mm3. While successful therapy is known to reduce AIDS events such as Pneumocystis jirovecii pneumonia and cerebral toxoplasmosis, the incidence of non-AIDS death has also declined since this therapy has been available (Mocroft A, unpublished data). It has thus been suggested that HIV may increase the risk of serious non-AIDS conditions and non-AIDS death. Obviously, ART may play a role in mediating some of this risk via toxicities as yet incompletely understood. We can look at non-AIDS morbidity broadly as two groups – ART toxicity-related events and non-ART toxicity-related events.
Non-AIDS events
We can break these down into the following groups:
Incidence of, and death from:
Malignancies End-stage renal disease Cardiovascular events Liver cirrhosis Death from:
Other non-AIDS causes (Mocroft A, unpublished data)
It is worth bearing in mind that there is a degree of overlap. Some malignancies may be HIV-related, as some renal, cardiovascular, and liver diagnoses may be HIV-related or related to the toxicities of ART. But how might HIV be implicated in the aetiopathogenesis of these conditions? In terms of general immune surveillance, it is known that at the time of HIV acquisition there is rapid early loss of CD4 T-cells in gut-associated lymphoid tissue (GALT). 2–6 Although the pathogenesis is not fully understood, there is evidence to suggest that this GALT CD4 T-cell depletion leads to loss of immunological and epithelial integrity of the mucosal barrier, allowing bacterial proteins to cross the gut wall more readily and cause broad activation of the immune system. 6 The state of generalized immune activation is thought to be associated with abnormal collagen deposition in lymph nodes, further impairing immune functioning. 7
With regard to malignancies, immunodeficiency leads to reduced control of oncogenic pathogens, such as human papilloma virus (HPV) and viruses from the herpes family – e.g. Epstein Barr (EBV) or human herpes virus 8 (HHV-8). There may be damage to tissues from infections and resultant chronic inflammation, known to be pro-oncogenic, and impaired circulating T-cells will have reduced ability to identify malignantly transformed cells.
In the kidney, apart from HIV-associated nephropathy (HIVAN) and HIV-related proteinuria, there may also be an immune link with other kidney pathologies (e.g. glomerulonephritides). High HIV RNA levels and low CD4 count may also predict raised creatinine levels and proteinuria. An elevated creatinine is associated with all-cause mortality in HIV-infected patients. 8
There has been a demonstrated association of HIV-infection with adverse changes in known or potential biomarkers for cardiovascular disease. HIV has been shown to be linked to HDL-cholesterol depletion, chronic inflammation (raised IL-6, highly sensitive C-reactive protein), endothelial activation dysfunction (VCAM, ICAM) and activation of coagulation (D-dimer). 9–11 All of these changes may be pro-atherogenic. Several of the changes appear to be at least partially reversed by ART, although ART itself has been associated with an effect on cardiovascular risk. 12
Immunodeficiency has been linked to more rapid progression of liver fibrosis in hepatitis B and C (HBV/HCV)-infected individuals. CD4+ and CD8+ responses to HBV/HCV are altered. HBV/HCV quasi-species may vary in the immunocompromised host and there is increased hepatocyte apoptosis.
Phillips et al.
13
discussed how HIV might increase the risk of serious non-AIDS conditions and non-AIDS death by looking at various types of evidence. These included:
Comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected persons; Studies of association between CD4 (and viral load) and risk of serious non-AIDS events; Randomized trials of the impact on serious non-AIDS events of reduction in HIV RNA level and increase in CD4 with ART.
Although all papers mentioning any of the above-mentioned serious conditions in addition to HIV have not been systematically reviewed, efforts were made to ascertain all the existing substantive studies providing one of these types of evidence regardless of the year of publication. Limitations of these data were also discussed. HIV-negative comparison groups differ from HIV-infected groups in more ways than just HIV infection (e.g. smoking) and adjustment for such confounding factors may not be possible. Each non-AIDS condition has its own set of risk factors that could act differently in HIV-infected people. HIV-infected subjects often comprise those on ART and ART naïve; hence, it is not possible in all studies to distinguish the effect of HIV from the effect of ART. Study data (from both cohorts and randomized trials) have been presented, which did show some (often conflicting) relationships between CD4 count non-AIDS disease. The FIRST,
14
DAD
15
and CASCADE
16
trials show an association between CD4 count and the risk of non-AIDS malignancy, while SMART
17
showed no significant difference. FIRST and DAD showed an association between CD4 count and renal disease/death, while SMART again showed no significant difference, although numbers of events were low. With regard to liver-related disease and death, FIRST showed no significant difference, while DAD, CASCADE and SMART did show a CD4 correlation.
We can look more closely at the risk of serious non-AIDS events in SMART. SMART was a large (>5000 participants), international randomized trial looking at CD4-guided treatment interruption. Subjects were randomized to a ‘viral suppression’ (VS) arm where they received continuous ART, or to a ‘drug conservation’ (DC) arm, where ART was stopped at CD4 counts above 350 cells/mm3 and restarted when the CD4 count fell below 250 cells/mm3. All serious non-AIDS events were higher in the DC compared with VS arm. Other non-AIDS deaths also showed significant increased risk (30 vs. 15). Of the 85 deaths that occurred in SMART, 45 (53%) were from non-AIDS diagnoses we have considered here (malignancies, end-stage renal disease, cardiovascular events, liver cirrhosis), while only seven (8%) were from AIDS-related diseases. 17 The hazard ratio (HR) for death from any other cause than opportunistic disease was 1.8 (1.1–2.9) in the DC arm compared with the VS arm, which fell to 1.2 (0.7–2.2) when adjusted for CD4 and viral load, indicating that immunosupression is associated with death from non-AIDS events. 17 The subset of patients (approximately 4% of participants) who were ART naive on entering SMART has been examined. There was a risk of serious non-AIDS events in SMART in ART-naïve patients or off-ART for ≥6 months, which was greater than those with suppressed HIV viral load in plasma. Twelve events occurred in those who deferred ART, while only two events occurred in those initiating ART immediately (VS arm), regardless of CD4 count (HR 7.02 [95% CI 1.57–3.14]). 18
On balancing the evidence, it seems that HIV may well play a role in several serious non-AIDS defining events. At higher CD4 counts, while the overall risk of disease is not high, non-AIDS events are much more common than AIDS events. The use of ART may reduce the risk of some serious non-AIDS events in those infected with HIV as well.
Research into new biomarkers may be key, as our current markers such as CD4 count are quite crude, with no functional or dynamic quality. Identifying biomarkers that mediate increased risk will provide insights into mechanisms of disease both related to HIV and beyond. One simplistic change may be that our previous CD4 cut-off of 200 cells/mm3 may be very low to prevent HIV-related morbidity. Certainly, national and international guidelines are now moving towards a higher CD4 count for initiating therapy. 19,20 Ongoing trials such as START will better address the question of when to start therapy. We now know that non-AIDS diseases are relatively common at higher CD4 count; SMART, while not powered to definitively address the question, suggests that the benefits of early ART outweighs the risks. ART in 2008 has a durable virological benefit and better tolerability. There is a theoretical cost benefit in reducing onward transmission risk using earlier ART, although some claim that the amount of onward transmission by those chronically infected may not be as important as transmission by those at primary infection who are unaware of their status and thus would not access care or treatment. It is, of course, important to balance these potential benefits with the risks of side-effects from long-term therapy. These may include expected side-effects and those which only come to light through long-term use. Potential side-effects may include lipid disturbances, myocardial infarction, osteopaenia, renal disturbances and central nervous system toxicities.
SUMMARY
To minimize the impact of HIV on such conditions, we must continue to try and diagnose HIV as early as possible. Research is needed into how to better predict these non-AIDS events in the context of HIV, both in those who are ART-naïve and ART-treated. The study of serious non-AIDS conditions is an important emerging area for HIV research. Research is needed to provide a basis for defining models of care for people with HIV, which take into account the risk of all serious conditions. Research into mechanisms by which HIV affects risk of non-AIDS conditions is needed, and it may help us understand more about the causes of such conditions outside HIV. The possibility that ART should be initiated much earlier should be investigated in a randomized trial. Such a trial will form a key resource for this new research area.