iconstar paper   HIV Articles  
Back grey arrow rt.gif
Cancers / HIV
  Download the PDF here
Strategic Timing of AntiRetroviral Treatment (START) Study Primary Results.........http://www.natap.org/2015/IAS/IAS_21.htm
START Trial: Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection......The START trial was designed and conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) A total of 4685 patients were followed for a mean of 3.0 years.....http://www.natap.org/2015/IAS/IAS_36.htm
Effects of immediate versus deferred initiation of antiretroviral therapy on bone mineral density: a substudyof the INSIGHT Strategic Timing of Antiretroviral Therapy (START) study.....http://www.natap.org/2015/AdverseReactComor/AdverseReactComor_01.htm
Bone Loss in HIV Persists Through Chronic Infection for Years - (02/16/16)



Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier combination antiretroviral therapy will alter this risk
Current Opinion in HIV & AIDS:
January 2014
The factors leading to an increased cancer risk among HIV-infected individuals remain poorly understood. Immunodeficiency and high prevalence of traditional cancer risk factors (e.g., smoking, oncogenic virus infection) [23-26] appear to be key, whereas evidence is emerging that a direct pro-oncogenic effects of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute [6,22,25,27]. It remains elusive, however, whether these factors act independently or synergistically. By reducing HIV replication, improving immune function and reducing inflammation at earlier stages of HIV infection, cART initiation at higher CD4+ cell counts has been proposed as a potentially effective approach for reducing NADM risk [6, 9,28,29]. The purpose of this review is to critically appraise recent evidence regarding established and suspected factors associated with cancer risk likely to be influenced by cART, including immunodeficiency, HIV viral load, enhanced inflammation and coagulation, cART toxicity, and the potential of earlier cART initiation to reduce this risk.
There is evidence that earlier cART initiation, by preventing immune deterioration associated with the decline in CD4+ cell counts, reduces KS and NHL risk [69-71]; indeed, cART initiation results in regression of early stage KS [72]. Furthermore, because cART improves immune function, lowers HIV viral load, and reduces inflammation, earlier cART initiation has been suggested as a potential approach for reducing NADM risk as well, among HIV-infected individuals [6,9,28,29]. Thus, reduced incidence [73, 74] and even regression of HPV-related pre-malignant squamous intraepithelial lesions [75] following cART initiation have been reported. Alongside their potential benefit in terms of cancer prevention through immune reconstitution and reduced inflammation and viral suppression, some drugs used in cART regimens have been found to have a direct anti-neoplasic effect. In in vitro and in vivo experiments, protease inhibitors were shown to block angiogenesis [76,77] and inhibit tumour growth and invasion [77]. Similarly, efavirenz was found to have selective anti-tumour cytoxic effects [78] and to inhibit proliferation and differentiation of neoplasic cells [79]. However, the clinical relevance of these findings is yet to be determined and, as discussed above, conflicting laboratory and epidemiological evidence suggests that some cART agents or classes may be associated with increased NADM risk.
The strong relationship between lower CD4+ count (i.e., immunodeficiency) and increased ADM risk is well-established
Some studies have reported an association between ongoing viral replication and cancer risk
More recently, evidence has emerged linking activated inflammatory and coagulation pathways, as demonstrated by higher plasma levels of biomarkers, to cancer risk. In The Strategies for Management of Antiretroviral Therapy (SMART) Study [46], structured cART interruptions were reciprocally associated with higher levels of coagulation and inflammatory biomarkers [47] and increased risk of cancer [48]. In a recent study of ours, we investigated the relationship between plasma levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, C-reactive protein (CRP), an inflammatory marker whose hepatic production is stimulated by IL-6, and D-dimer, a fibrin-degradation product and marker of enhanced coagulation, and the risk of cancer among 5,000 HIV-infected individuals enrolled in the control arms (i.e., standard of care) of three randomized trials [22]. Increasing baseline biomarker plasma levels were independently associated with higher cancer risk; the hazard ratio (HR) per doubling in biomarker level was 1.38 (P < 0.001) for IL-6, 1.16 (P = 0.001) for CRP, and 1.17 (P = 0.03) for D-dimer. Results were similar for infection-related and infection-unrelated cancers. This association was strongest for IL-6, the only biomarker that remained significantly associated with cancer risk with simultaneous adjustment for all three markers. Although not providing definitive evidence for a causal link between enhanced inflammation/coagulation and cancer risk during HIV infection, these findings do indicate that trials of interventions that reduce inflammatory and coagulation biomarker levels, in particular IL-6, may be warranted.
cART is, however, not without risks and there is no conclusive laboratory or epidemiological evidence regarding the association of cART and NADM risk. Therefore, continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. Since cART alone only partly normalizes the enhanced inflammation and coagulation associated with HIV infection, the role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce NADM risk deserves further investigation.
With regard to cART toxicity as a risk factor for cancer, a number of studies have failed to detect positive associations between cART use and cancer risk [49-52]. Furthermore, the beneficial effects of cART on HIV replication, immune function, and inflammation suggest that cART use would lead to a reduction in overall cancer risk [6,9,28,29].
Nevertheless, potential carcinogenic effects of specific cART agents and drug classes may result in increased risk of cancer. This is the case not only for toxic, older drugs, such as zidovudine [53,54], but also for antiretrovirals currently recommended as first-line therapy for treatment-naÏve patients. Protease inhibitors have been linked to a higher risk of anal cancer in observational studies after adjustment for important confounders [55-57] and efavirenz, a non-nucleoside reverse transcriptase inhibitor, was associated with increased risk of Hodgkin lymphoma in one study [58]. In a recent report, raltegravir, an integrase inhibitor, was found to induce host DNA rearrangements, which, from a theoretical point of view, may have unforeseen consequences including an increased risk of cancer [59]. It is also biologically plausible that, by reducing immunological surveillance of malignant cells, CCR5 inhibitors, a drug class increasingly used in treatment-experienced individuals who failed previous cART regimens, may also lead to an increased incidence of NADM [60]. However, in the absence of any epidemiologic evidence, the clinical relevance of the potential carcinogenic effects of integrase and CCR5 inhibitors remains to be determined.
Key Points
⋅ Cancer, in particular non-AIDS defining malignancies (NADM), imposes a growing burden on HIV-infected individuals. Immunodeficiency appears to be key to the increased cancer risk observed in this population, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and combination antiretroviral therapy (cART) toxicity may also contribute.
⋅ Because cART improves immune function, lowers HIV viral load, and reduces inflammation, cART initiation at higher CD4+ cell counts has been proposed as a potentially effective approach to reducing NADM risk.
⋅ Nevertheless, cART only partly normalizes the enhanced inflammation associated with HIV infection and conflicting laboratory and epidemiological data have been reported as to if (and how) cART affects cancer risk.
⋅ Continuous epidemiological surveillance is warranted to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce cancer risk deserves further investigation.

  iconpaperstack View Older Articles   Back to Top   www.natap.org