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It is accepted that populations in the so-called developed world have gone through an ‘epidemiological transition’ where chronic disease has replaced infection as the primary cause of death. However, there is mounting evidence that infections play a key role in certain chronic diseases such as cancer. Cancers of infectious origin provide the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. Worldwide, one in every five malignancies can be attributed to infections: this figure is considered conservative and expected to rise. About two-thirds of these cancers occur in less developed countries. The majority of these malignancies are recognised to be caused by viruses via mechanisms of chronic inflammation, immunosuppression or the expression of oncogenic proteins. An understanding of virally mediated carcinogenesis may provide new targets for the development of specified viral therapy that not only impacts on viral infections but human cancer as well. From a public health perspective, viral carcinogenesis is important because it shows potential for preventative and therapeutic programmes to reduce the burden of cancer, particularly in less developed countries.

Introduction

The process of carcinogenesis involves multiple contributing factors. These include environmental, lifestyle, host factors, genetically inherited traits and infectious agents. Infectious agents are important from a public health aspect as they represent a significant and preventable cause of cancer. The infection-attributable cancer burden has been estimated at 1.9 million cases, or 17.8% of the total global cancer burden. [1] The percentage of infection-attributable cancer is higher in developing countries (26.3%) than in developed countries (7.7%), reflecting the higher prevalence of infectious diseases. Of these infection-associated cancers, viruses are the most common causative agents with 12.1% of cancers worldwide attributed to viral infections. [1]

This article aims to outline current knowledge of the role of viruses in mediating cancer, explore the main mechanisms involved and propose exciting preventative and therapeutic approach for virus-associated cancers in the 21^st century.

Mechanisms by which viruses mediate cancer

The International Agency for Research on Cancer (IARC) recognises seven viral agents that have been linked with cancer: Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), Karposi-Sarcoma Herpes Virus (Human Herpes Virus 8), Human T-cell leukemia virus type I (HTLV-1) and Human Immunodeficiency Virus type 1 (HIV). [2] These seven viruses classified as ‘carcinogenic to humans’, and the recently discovered Merkel Cell Virus which has not yet been included by the IARC, are summarised in Table 1.

The induction of cancer development by viruses requires persistent infection of the host.  It is hypothesised that long-term infection initiates cellular changes that predispose to cancer progression. [3]

In addition to persistent infection, the specific actions of these viruses are discussed below and can be broadly grouped into viruses that induce cancer by (i) chronic inflammation (eg. HCV), (ii) immunosuppression (eg. HIV) and by (iii) direct actions of viral oncogenic proteins (eg. EBV, HPV). [3]

(i) Cancer associated with chronic inflammation: Hepatitis B and C Viruses

Once a viral infection is initiated, recovery requires the activation of the innate and adaptive arms of the immune system. Acute inflammation is usually a short process that eliminates the pathogen. However, chronic inflammation may result if acute inflammation continues unresolved and fails to eradicate the pathogen. Chronic inflammation itself may promote carcinogenesis via the release of many factors including nitric oxide, cytokines and chemokines thus mediating DNA damage and effecting cell proliferation and neoangiogenesis. [3]

HBV and HCV infections are examples of chronic infections associated with ongoing inflammation. HBV and HCV are responsible for 54% and 31% of human hepatocellular carcinoma (HCC) cases worldwide. [4,5] These hepatotropic viruses can induce cirrhotic livers from which HCC can arise. This review will focus on HCV.

In those infected with HCV, 80% will develop chronic infection, and in 30 years 10-30% of these chronic HCV infections will develop cirrhosis. The subsequent rate of cirrhotic HCV liver disease developing HCC is 1-3% per year. [6] Since current WHO estimates suggest that 3% of the world’s population, or 150 million people, are HCV infected, this represents a significant virus-associated cancer burden.

HCV is a RNA virus of the hepacivirus family of the genus Flaviviridae. HCV does not integrate itself into the host genome and several viral proteins (core protein and the NS3, NS4B and NS5A) have been suggested as potential oncogenic candidates in-vitro. For example, the HCV NS5A protein has been shown to bind and sequester the cellular p53 protein to the perinuclear membrane, and it may be the be key to HCC development. [7] However, it is thought that HCC primarily occurs due to repeated rounds of hepatocyte destruction and regeneration from chronic inflammation, producing a procarcinogenic cirrhotic microenvironment, [3,8] rather than through the action of viral oncogenes. Cirrhosis appears to be the main risk factor for HCC, but exogenous factors could also play a role, such as chronic alcohol consumption, viral co-infection (such as HIV modulating immunosuppression), diabetes and obesity [4] highlighting the multifactorial triggers for the induction of cancer. [9]

HCV is also a well-established cause of essential mixed cryoglobulinemia, a lymphoproliferative disease that can evolve into B-cell non-Hodgkin lymphoma (NHL). [10] HCV has been suggested to be lymphotropic, but this is not well defined. [11] Again, since HCV has not been demonstrated to encode direct oncogenic proteins, the mechanisms of HCV-induced NHL are likely to be via chronic inflammation.

(ii) Cancer associated with immunosuppression and insertional mutagenesis: HIV

It is estimated that there are approximately 34.2 million individuals worldwide living with HIV infection, two-thirds of these being in sub-Saharan Africa. [12] People with HIV have a substantially higher risk of certain cancers compared with uninfected people of the same age. These cancers are termed AIDS-defining malignancies and include: Kaposi sarcoma, a mesenchymal tumour originating from lymphatic endothelial cells, cervical cancer and NHL. [13] Additionally, other types of cancer, such as Hodgkin’s disease (HD), anal cancer, lung cancer and testicular germ cell tumours appear to be more common among HIV-infected subjects compared to the general population and are termed AIDS-associated cancers. [14]

HIV is an RNA lentivirus of the Retroviridae family. The members of this family all integrate into the host chromosome and thus have the potential to cause direct insertional mutations or activation of cellular oncogenes.  Other members of the Retroviridae family, such as Mouse mammary tumour virus (MMTV) have a well-defined link with tumours in mice, which are likely mediated by insertional activation of cellular genes in breast tissue through hormone responsive elements in the MMTV promoter. [15] Similarly, insertional mutagenesis and the induction of lymphoma has been identified in humans treated with gammaretrovirus [16] and lentivirus vectors used in gene therapy. [17] In contrast, there is little evidence for an HIV oncogenic protein, although studies have suggested that the transactivator protein of viral gene expression, Tat, which has oncogenic potential, is secreted by HIV. It has also been suggested that Tat can re-enter non-infected cells blocking apoptosis and accelerating tumour formation. [18]

The above described AIDS-associated cancers are linked with low CD4+ T-cell counts, and this may lead to co-infections with other oncogenic viruses such as HPV (cervical cancer) and Kaposi’s sarcoma-associated herpesvirus (Kaposi’s sarcoma), or the reactivation of existing infections with opportunistic oncogenic viruses such as EBV (Burkitt’s lymphoma). [18] However, the specific mechanisms by which depressed immunity may increase the risk for cancer are unclear, except for KS and most subtypes of NHL that are strictly associated with a low CD4 count. [19] Supporting the link between cancer and immunosuppression, the pattern of cancers in immunosuppressed organ transplant recipients is similar to people with HIV/AIDS. [20]

Thus, the evidence suggests that HIV can be associated with carcinogenesis through insertional mutagenesis. Moreover, HIV may indirectly cause cancers by inducing a chronic state of immunosuppression, reducing immunosurveillance for neoplastic cells, and increasing the risk of reactivation of latent oncogenic viruses as well as the risk of acquiring new oncogenic viral infections.

(iii) Cancer associated with Oncogenic viruses

Of the identified and accepted carcinogenic viruses, EBV, HHV-8, HTLV-1and HPV are tumour viruses that express viral oncogenic proteins to exert carcinogenesis. HBV also produces the HBx protein that disrupts signal transduction and deregulates cell growth: however, HBV-associated carcinogenesis is believed to be mainly mediated through chronic inflammation as described for HCV. [3] Oncogenic viruses can transform cells by carrying viral oncogenes into a cell or by activating cellular proto-oncogenes. [5] The virally derived oncogenes produce transforming growth factors that deregulate growth control and proliferation, leading to malignant transformation. Specific examples are discussed below, with the oncogenic viruses divided into DNA and RNA tumour viruses.

DNA Tumour Viruses

EBV best illustrates DNA tumour viruses. EBV is a double-stranded DNA virus of the herpesviridae family, and causes infectious mononucleosis. Like all herpesviruses, EBV causes a life-long latent infection, and EBV is the primary cause of B-cell transformation in Burkitt’s lymphoma. [14] This was the first human tumour associated with an infectious agent. Since then, EBV has been implicated in a number of other cancers (see Table 1).

In the case of EBV-lymphoma, expression of the viral oncogene, latent membrane protein-1 (LMP1), transforms cells into lymphoblasts by the disruption of cellular signal transduction. [3] In contrast, in most NPCs, the viral BamHI-A reading frame-1 (BARF1) gene is expressed. BARF1 has been identified as an important oncogene in NPC pathology. [21] Thus, EBV has a number of different oncogene expression profiles associated with different cancers. EBV is extremely widespread in prevalence affecting more than 90% of the world’s population, [22] yet only a small fraction of the infected populations have a cancer attributable to EBV.  Therefore, beside viral factors, host responses also play a role in the neoplastic transformation of EBV-infected cells.

HHV-8 is a DNA virus of the herpesviridae family, and HHV-8 infection is strongly associated with Kaposi’s sarcoma. The mechanism, however, of HHV-8-induced carcinogenesis is very different to that of the related virus, EBV. HHV-8 infects endothelial cells and encodes a viral G protein-coupled receptor (vGPCR). This vGPCR has dysregulated signalling function and acts as an oncogene, inducing angioproliferative tumours. [23]

HPV is a DNA virus of the papillomavirus family, and there are 30-40 types. Approximately fifteen types of HPV are oncogenic viruses, causing 5.2% of total human cancers. [24] These cancers include those of the ano-genital mucosae (cervix, vagina, vulva, anus and penis), and the mouth and the pharynx. [24,25] The predominant transmission of these HPV infections is sexual. [26] While HPV is an accepted aetiological factor for oral and pharyngeal cancers, the major risk factors are tobacco and alcohol, with the effects of these exposures being multiplicative. [25] Oncogenic HPV can be detected by PCR in virtually all cases of cervical cancer, with specific genotypes HPV16 and 18 identified as the primary causes of cervical cancer. These viral genotypes have also been associated with 86-95% of HPV-associated non-cervical cancers. [26,27] These viruses infect the basal layer of the stratified epithelium and express two important viral oncoproteins, E6 and E7. [23] These proteins destabilise the cellular tumour suppressor genes, p53 and the retinoblastoma protein (RB). [28] This dysregulation of cellular growth directly leads to cell transformation and cancer.

RNA Tumour Viruses

HTLV-I is a retrovirus related to HIV, which is associated with adult T-cell leukaemia. Only 1% of HTLV-I infected individuals will develop leukaemia, and only after a long latency period of 20-30 years. [29] HTLV-I infection rates are elevated in certain Indigenous populations of Central and Northern Australia, as well as the southern islands of Japan, the Caribbean basin and South Africa. [14] Unlike HIV, HTLV-I infections are not associated with immunosuppression, but HTLV-I encodes an oncogenic protein; the viral Tax protein. [30,31] Tax is a transcription factor and is known to bind to a number of cellular genes involved in cell cycle progression and growth regulation, such as NFkB and p53. [32] Via promotion of transcription and cell cycle progression, Tax is proposed to set up a self-stimulating loop that causes continuous proliferation of infected T-cells, and ultimately leukaemia.

The growing cancer burden attributable to viruses

While there are only seven viruses clearly recognised as carcinogenic to humans, this is conservative, with the discovery of new associations between infections, particularly viruses, and cancer anticipated.

MCV is a recently discovered DNA virus that is found to be associated with approximately 80% of Merkel Cell Carcinomas, an aggressive form of skin cancer. [33] MCV is a relatively common virus, yet only leads to cancer in rare circumstances. It is thought that this is because for MCV to become carcinogenic, two rare mutagenic steps must occur:  viral integration and T antigen mutation. Integration of MCV is not a regulated event, unlike for HIV and HTLV-I, and occurs rarely. The integration, probably of only parts of the MCV genome into cells, renders the virus replication-incompetent, but allows parts of the virus, such as the T-antigens, to be maintained in these cells. [34] MCV T antigens can be oncogenic, and target cellular tumour suppressors and cell cycle regulatory proteins. Thus, the whole replicative virus may not be present, but the residual oncogenic T-antigen is, and can promote transformation of the cell leading to cancer.

Cancerous cells themselves are generally not transmissible. In humans, during the two known physiological routes for tumour cell transmission (pregnancy and organ transplantation), the immune system is altered.  Transplacental transmission of lymphoma, acute leukaemia, melanoma and carcinoma have been observed, as well as acute leukaemia cells transmitted to the foetuses in multiple case pregnancies with the subsequent disease development in the newborn. [35] Similarly, in organ transplantation, donor derived tumour cells have been observed, with the immunosuppressive therapy following transplantation potentially facilitating the engraftment and growth of donor derived tumour cells. [35] Fortunately, these transmissible tumours are rare, with the development of donor-derived tumours in solid organ transplant recipients at 0.04%. [15] Additionally there have been rare case reports of human contagious cancers documented via needle stick (colonic adenocarcinoma), [36] and a surgeon contracting a malignant fibrous histiocytoma from a patient following an intraoperative cut to his left palm. [37]

Cancer prevention and public health strategies

In theory, the cancers resulting from viral infections represent an exciting potential for public health intervention strategies and therapeutics to prevent these cancers.  In particular, the high number of cancers attributable to viral infections in developing countries presents a real need and opportunity for public health programs to reduce both infectious disease and cancer burden. [38]

The mode of transmission of the seven IARC-recognised carcinogenic viruses is provided in Table 2. The implementation of public health education, awareness, treatment and prevention programs to reduce the horizontal spread of these viruses and manage these viral infections in patients is a public health priority, but has the additional benefit of reduction in the associated cancer risks.

Public health programs should be prioritised to target vertical transmission of viral infections such as HBV and HIV. The WHO outlined targets and recommendations in 2010 with the prevention of mother to child transmission (PMTCT) strategy, targeting anti-retroviral therapy (ART) in pregnant women and providing guidelines for HIV in relation to infant breastfeeding. [39] Similar guidelines may be applicable to our Indigenous population afflicted by HTLV-I, which has a well described increased mother to child transmission rate associated with breastfeeding. [40] However, breastfeeding recommendations in resource poor settings need careful consideration. [41]

More outstanding, are the successful programs for screening and management of viral infections associated with cancer. For example, the National Cervical Screening Program (NCSP) in Australia has had a huge benefit in reducing the mortality rates from cervical cancer from 3.9/100,000 in 1991 to 1.9/100,000 in 2007, [42], demonstrating that cancer prevention via monitoring oncogenic viral infections is a real possibility. [43] Additionally, such programs as the NSW Cancer Council ‘B positive’ program, implemented in 2008 aims to increase HBV awareness and the treatment and management of chronic HBV infection to reduce the risk of HCC. [44]

Vaccination and treatments to prevent cancer-associated viral infections

Historically, the world has experienced, with polio and smallpox, elimination or virtual elimination of viral diseases through vaccination. There are now vaccines available for both HBV and HPV, two major infectious causes of HCC and cervical cancer, respectively. The HBV surface antigen is the basis for the vaccine against the HBV, which was first available in the 1980s, and is the first vaccine for prevention of a human cancer. [45] Vaccination programmes of children with the HBV vaccine have already proved successful in protecting against chronic carriage and HCC, [46,47] and HBV vaccination has now been introduced into the Australian childhood immunisation schedule. Long-term and full coverage of newborns against HBV has the potential of reducing HCC by approximately 85%. [14]

The two currently marketed vaccines for HPV utilise the L1 coat protein in the form of virus-like particles to prevent persistent infection with HPV16 and HPV18. [48-50] These viral subtypes are estimated to cause 71.8% of all HPV-related cancers, cervical and non-cervical. [25] These vaccines need to be administered prior to exposure to HPV16 and 18, which makes delivery in a public health setting more difficult than an infant setting. In Australia in 2007, the National HPV vaccination Program was made available to teenage women, and is now part of the school age vaccination program. From 2013 will also be made available to 12-13 year old males. [51] However, the current cost is not practical for all groups, especially those in developing countries, [14] and although the HPV vaccination program in developing countries is supported by the WHO, the applicability and benefits of HPV vaccination have been queried and recently suspended in India. [52] The efficacy of these HPV vaccines in preventing infections at sites other then the cervix, vagina and vulva should be assessed. [27] Specifically, research is required on the administration to high-risk groups (e.g. men who have sex with men and HIV positive people) for anal cancer. [24]

Unfortunately, the described RNA viruses associated with cancer, HIV and HCV, are highly genetically variable and therefore prove to be difficult candidates for prophylactic vaccines. For these viruses, anti-viral therapy appears to be more successful. For example, the risk of infection-associated cancers in HIV positive individuals is related to ongoing HIV replication. The use of suppressive highly active antiretroviral therapy (HAART) has dramatically reduced the risk for opportunistic infections and improved overall life expectancy in patients with HIV-infection and AIDS. [53] A significant decrease in the incidence of KS has been observed in patients treated with HAART. [19] Moreover, HAART and preserved CD4 count preferentially reduces the risk of malignancies associated with oncogenic infections. [54] Similarly, patients with HCV who were prescribed the anti-viral agent, interferon, showed regression of their splenic lymphoma. [55]

Recently approved HCV NS3-4A protease inhibitors are proving effective in clearing and curing HCV infection. In the future, this may significantly impact on HCV infection rates and subsequent incidence of HCC.

Exciting Therapeutic Targets

Our understanding of mechanisms of viral initiation of carcinogenesis has provided the opportunity to design innovative, targeted cancer therapies based on the pathways disrupted by the transforming viral genes.

For example, recent studies reveal that the cellular survivin oncoprotein is activated by MCV large T antigen protein via targeting the cellular Rb (p53) protein, and that survivin inhibitors can delay MCV-induced tumour progression in animal models. [56] Clinical trials are now in progress to determine whether these survivin inhibitors have any therapeutic benefits. Additionally, MCV is a target for cell-mediated immune responses, and so important research efforts are being focused on immunologic therapies that may benefit MCC patients. [56] These findings provide a proof of principle for specifically treating virus-associated cancers by targeting the mechanisms by which they induce oncogenesis. In the case of MCV, a promising rational drug target has been uncovered within only four years of the initial discovery of MCV as a causative cancer agent. Similarly, other new treatments for cancer might be rapidly developed should we identify new viral associations with malignancies.

Conclusion

Viruses are an important aetiological cause of human cancers, especially in the developing world where they lead to a significant burden of disease.  Although viruses make an important contribution to human cancer development, it is often difficult to prove the association of viral infections with cancer, due to latency in tumour development and the multifaceted interaction with the host.  It is reasonable to think that the calculations of cancers attributable to viruses are underestimates and that cancers other than the ones described may also be associated with viral infections. The viruses in this review exemplify the best-established human tumour viruses, but there are many other potential candidates.  Undoubtedly, as our knowledge of carcinogenesis and viruses expand, further cancer-associated viruses will be discovered. From a public health point of view, infectious diseases are often preventable or treatable; therefore, cancers associated with infections are, or may become, preventable.  Prevention may be in the form of vaccination, novel therapies to target the immune system or oncogenic proteins, or education and public health interventions.

Conflict of interest

None declared.

Correspondence

V Boon: boon0035@flinders.edu.au

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Laser photocoagulation has remained the standard of treatment for diabetic macular oedema (DME) for the past three decades. However, it has been shown to be unbeneficial in chronic diffuse DME. Intravitreal bevacizumab (ivB) has been proposed as an alternate and effective treatment of DME. This review evaluates the evidence behind comparing bevacizumab to laser photocoagulation in treating persisting DME. A structured systematic search of literature, with critical appraisal of retrieved trials, was performed. Four randomised controlled trials (RCTs) supported beneficial effects of ivB over laser photocoagulation. Only one RCT, the BOLT study, compared laser to ivB effect in persistent DME. The results from the study showed significant improvement in mean best corrected visual acuity (BCVA) and greater reduction in mean central macular thickness (CMT) in the ivB group, with no significant difference in safety outcome measures.

Introduction

Diabetic macular oedema is a frequent manifestation of diabetic retinopathy and is one of the leading causes of blindness and visual acuity loss worldwide. [1] The presence of DME varies directly in proportion with the duration and stage of diabetic retinopathy, with a prevalence of three percent in mild non-proliferating retinopathy, 38% in moderate-to-severe non-proliferating retinopathy and 71% with proliferative retinopathy. [2]

Diabetic macular oedema (DME) is a consequence of micro-vascular changes in the retina that lead to fluid/plasma constituent accumulation in the intra-retinal layers of the macula thereby increasing macular thickness. Clinically significant macular oedema (CSME) is present when there is thickening within or close to the central macula with hard exudates within 500μm of the centre of the macula and with retinal thickening of at least one disc area in size. [3,4] As measured in optical coherence tomography, central macular thickness (CMT) corresponds approximately to retinal thickness at the foveal region and can quantitatively reflect the amount of CSME a patient has. [5] Two different types of DME exist: focal DME (due to fluid accumulation from leaking micro-aneurysms) and diffuse DME (due to capillary incompetence and inner-retinal barrier breakdown).

Diabetic macular oedema pathogenesis is multi-factorial; influenced by diabetes duration, insulin dependence, HbA1C levels and hypertension. [6] Macular laser photocoagulation has remained the standard treatment for both focal and diffuse DME, based on the recommendations of the Early Treatment Diabetic Retinopathy Study (ETDRS) since 1985. This study showed the risk of CSME decreases by approximately 50% (from 24% to 12%) at three years with the use of macular laser photocoagulation. However, the improvement in visual acuity is modest, observed in less than three percent of patients. [3]

Recent research indicates that macular laser therapy is not always beneficial and has limited results, especially for chronic diffuse DME, [3,7] with visual acuity improving in only 14.5% of patients. [8] Following laser treatment, scars may develop and reduce the likelihood of vision improvement [3] hence alternate treatments for DME such as intravitreal triamcinolone (ivT), have been investigated. Intravitreal triamcinolone (ivT) works via a number of mechanisms including reducing vascular permeability and down regulating VEGF (vascular endothelial growth factor). Anti-VEGF therapies have been the focus of recent research, and those modalities have been shown to potently suppress angiogenesis and to decrease vascular permeability in ocular disease such as DME, leading to improvement in visual acuity. [9] The results of treating DME with anti-VEGFs are controversial and are in need of larger prospective RCTs. [10]

Currently used anti-VEGFs include bevacizumab, ranibizumab and pegatanib. Ranibizumab has been shown to be superior in treating DME, both in safety and efficacy, compared to laser therapy, in several studies that include RESTORE, RESOLVE, RISE and RIDE studies. [11-13] It has been recently approved by the Food and Drug Administration (FDA) for treating DME in the United States of America. [14] Bevacizumab (Avastin®) is a full length monoclonal antibody against VEGF, binding to all subtypes of VEGF. [10] In addition to treating metastatic colon cancer, bevacizumab is also used extensively off-label for many ocular conditions that include age related macular degeneration (AMD), DME, retinopathy of prematurity and macular oedema secondary to retinal vein occlusion. [15] Documented adverse effects of ivB include transiently elevated intraocular pressure (IOP) and endopthalmitis. [16] Systemic effects associated with ivB injection include rise in blood pressure, thrombo-embolic events, myocardial infarction (MI), transient ischemic attack and stroke. [16,17] Other significant adverse events of bevacizumab when given systemically include delayed wound healing, impaired female fertility, gastrointestinal perforations, haemorrhage, proteinuria, congestive heart failure and hypersensitivity reactions. [17] Although not currently approved, a 1.25-2.5mg infusion of ivB is used for treating DME without significant ocular/systemic toxicity. [15]

The DRCR.net study (2007) has shown that ivB can reduce DME. [18] In addition, several studies, which have been carried out on diabetic retinopathy patients with CSME evaluating the efficacy of ivB ± ivT versus laser, demonstrated better visual outcomes with BCVA. [6,19- 21] Meta-analysis of those studies indicated ivB to be an effective short-term treatment for DME, with efficacy waning after six weeks. [6] This review evaluates the evidence behind the effect of ivB, compared to laser, in treating persisting DME despite standard treatment.

Clinical question

Our clinical question for this focused evidence based medicine article has been constructed to address the four elements of the problem, the intervention, the comparison and the outcomes as recommended by Strauss et al. (2005) [22]. “In diabetic patients with persistent clinically significant macular oedema (CSME) is intravitreal Bevacizumab (Avastin®) injection better than focal/grid laser photocoagulation in preserving the best-corrected visual acuity (BCVA)?”

Methodology

Comprehensive electronic searches in the British Medical Journal, Medical Journal of Australia, Cochrane Central Register of Controlled Trials, MEDLINE and PUBMED were performed for relevant literature, using the search terms diabetic retinopathy, CSME, CMT, bevacizumab and laser photocoagulation. Additional information from the online search engine, Google, was also incorporated. Reference lists of studies were then hand-searched for relevant studies/trials.

Selection

Results were restricted to systematic reviews, meta-analysis and randomised clinical trials (RCTs). Overall six RCTs were identified, which evaluated the efficacy of ivB compared to lasers in treating DME. [18- 21,23,24] There was also one meta-analysis comparing ivB to non-drug control treatment (lasers or sham) in DME. [7] One study was published showing pilot study results of the main trial, so the final version was selected for consideration to avoid duplication of results. [20,23] One study was excluded because it excluded focal DME patients. [19] The DRCR study (2007) was excluded because it was not designed to evaluate if treatment with ivB was beneficial in DME patients. [18] A meta-analysis by Goyal et al. was also excluded because it evaluated bevacizumab with sham treatment and not laser therapy. [7]

Thus, three relevant RCTs were narrowed down for analysis (Table 1) in this evidence based medicine review. [20,21,24] However, only the BOLT study (2012) evaluated the above treatment modalities in persistent CSME. The other two RCTs evaluated the treatment efficacies in patients with no prior laser therapies for CSME/diabetic retinopathy. Hence, only the BOLT study (2012) has been critically appraised in this report. The study characteristics of the other relevant RCTs evaluating ivB versus lasers are represented in Table 1, and where possible will be included in the discussion.

Outcomes

The primary outcomes of interest are changes in BCVA and CMT, when treated with ivB or lasers for DME, whilst the secondary outcomes are any associated adverse events. All three studies were prospective RCTs with NHMRC level-II evidence. Table 1 summarises the overall characteristics of the studies.

Critical appraisal

The BOLT Study (2010) is a twelve month report of a two year long single centre, two arm, randomised, controlled, masked clinical trial from the United Kingdom (UK). As such, it qualifies for NHMRC [25] level-II quality of evidence. It is the only RCT that compared the efficacy of ivB with laser in patients with persistent CSME (both diffuse and focal DME) who had undergone at least one laser therapy for CSME previously. Comparison of study characteristics of the three RCTs chosen are presented in Table 2.

Major strengths of the BOLT Study compared to Soheilian et al. and Faghihi et al. studies include the duration of study and increased frequency of review of patients in ivB groups. The BOLT Study was a two year study, whereas the other two studies’ duration was limited to less than a year (Table 1). Because of its lengthy duration, it was possible to evaluate the safety outcome profile of ivB in the BOLT Study, unlike in the other two studies.

Research has indicated that the effects of ivB could last between two to six weeks, [6] and the effects of lasers could last until three to six months. [3] In BOLT, the ivB group was assessed every six weeks, and re-treatment provided with ivB as required, while the laser group were followed up every four months ensuring the preservation of efficacy profile and its reflection in the results. Whereas, in Sohelian et al., [20] follow up visits were scheduled every twelve weeks after the first visit, and in Faghihi et al., [21] follow up was at six and sixteen weeks. Therefore, there may have been a bias against the efficacy profile of ivB, given the insufficiency in the nature of follow up/treatment. Apart from the follow up and therapy modalities, the groups were treated equally in BOLT, preserving the analysis against treatment bias.

Weaknesses of the BOLT Study [24] include limited number of patients: 80 eyes in total, with 42 patients allocated to ivB and 38 patients to laser therapy. Of them, in the ivB group, six patients discontinued intervention; only 37 patients were included in the analysis at 24 months and five were excluded as the data was not available. Similarly, of the 38 patients allocated to the laser group, 13 patients discontinued the intervention; 28 patients were analysed overall where ten were excluded from analysis. However, the BOLT Study performed intention to treat analysis minimizing dropout effects. Given these, we feel the BOLT Study fulfills the criteria for a valid RCT with significant strengths.

Magnitude and precision of treatment effect from BOLT Study

Best corrected visual acuity outcomes

Significant difference existed between mean ETDRS BCVA at 24 months in the ivB group (64.4±13.3) compared to the laser group (54.8±12.6) with p=0.005 (Any p-value <0.05 indicates statistical significance between the groups under comparison). Furthermore, the study reports of the ivB group gaining a median of 9 ETDRS letters whereas the laser group gaining a median of 2.5 letters (p=0.005). Since there was a significant difference between the duration of CSME between the two groups, the authors of the study performed analysis after adjusting for this variable. They also adjusted for the baseline BCVA and for patients who had cataract surgery during the study. The mean BCVA still remained significantly higher in the ivB group compared to laser.

Marked difference has also been shown in the proportion of people who gained or lost vision between the two treatment groups. Approximately, 49% of patients in the ivB group gained more than or equal to ten ETDRS letters compared to seven percent of patients in laser group (p-value = 0.01). Similarly, none of the patients in the ivB group, compared to 86% in the laser group (p=0.002), lost fewer than 15 ETDRS letters. In addition, the study also implied that BCVA and CMT can be maintained long term with reduced injection frequency of six to twelve months. However, the authors also suggest that increasing the frequency of injections to every four weeks (rather than the six week frequency opted in the study) may provide better visual acuity gains as reported in RISE and RIDE studies. [13]

Central macular thickness outcomes

The mean change in the CMT over the 24 month period was -146±171μm in ivB group compared to -118±112μm in the laser group (p=0.62), showing statistically no significant difference in ivB/laser effectively reducing the CMT. This differed from the twelve month report of the same study that indicated improvement in CMT in the ivB group compared to the laser group.

Retinopathy

Results of the BOLT Study indicated a trend of reducing retinopathy severity level in the ivB group, while the laser group showed stabilised grading. However, the Mann-Whitney test indicated no significant difference between the groups (p=0.13). [24]

We summarised the results of the author’s analysis of the step-wise changes in retinopathy grading levels, for further analysis, into three categories: deteriorating, stable and improving (Table 3). As shown in the table, we calculated the p-values using the chi-square test between both groups for each category.

We attempted to further quantify the magnitude of ivB treatment compared to lasers on the retinopathy severity level by calculating the number needed to treat (NNT) using the data in Table 3. The results showed an absolute risk reduction of nine percent with an NNT of 10.9 (95% CI indicating harm in 21.6 harm to benefit in 3.6 patients treated). Since the confidence interval indicates an uncertainty between benefit and harm, this trial does not give sufficient information to inform clinical decision making regarding change in retinopathy severity levels with ivB treatment.

Safety outcome measures

As mentioned, one of the strengths of the BOLT Study is evaluating the safety profile of ivB given its two year duration. The study analysed the safety outcomes of macular perfusion and retinal nerve fibre layer (RNFL) thickness in detail. The results indicated no significant difference in the mean greatest linear diameter of foveal avascular zone between the laser and the ivB group, from baseline or in the worsening of severity grades. Similarly, no significant changes in median RNFL thickness have been reported between ivB and laser groups.

At 24 months, the number of observed adverse events, ocular and systemic, in the study was low. We have analysed the odds ratio (Table 4) as per the published results in the study. Statistically significant higher chances of having eye pain and irritation (eighteen times greater risk) during or after intervention, sustaining sub-conjunctiva haemorrhage and of having a red eye (eighteen times greater risk) was found in the ivB group compared to lasers. As can be further inferred from the table, no significant differences in sustaining other non-ocular adverse events, ocular serious adverse events or non-ocular serious adverse events including stroke/MI/other thrombo-embolic events were found between both the groups.

Clinical applicability of results

The BOLT Study participants were from Moorfields Eye Hospital (UK) and had comparable demographics and healthcare standards to Australia. In the study, both patient (BCVA, retinopathy severity level changes, adverse events) and disease-oriented outcomes (CMT) were considered, making the study both theoretically and practically relevant, informing both clinicians and researchers of the outcomes. Given this, clinical applicability of the results to the Australian population appears reasonable. All other personnel involved in the study (outcome assessors) and imaging technology are available as well, making the treatment feasible in our setting.

In Australia, the overall diabetic retinopathy prevalence is 24.5%, [6] the statistics associated with it rise every year due to the progressing obesity/diabetes epidemic. Bevacizumab is currently approved under the pharmaceutical benefits scheme for metastatic colon cancer.

It is being successfully used ‘off-label’ for the treatment of ocular conditions including age related macular degeneration and diabetic macular oedema. It costs about 1/40th the cost of ranibizumab, another anti-VEGF drug that has current approval for AMD treatment in Australia and FDA approval for DME treatment in America. [26] Since recent studies indicate no superior effect of ranibizumab versus bevacizumab in safety and efficacy profile in preserving visual acuity, [27,28] and since recent NICE guidelines also recommend not using ranibizumab for diabetic macular oedema due to high costs involved with the administration of that drug, [29] bevacizumab must be further considered and evaluated for cost effectiveness in routine usage in clinical practice.

Given the benefits with ivB, that is, improved BCVA, no significant adverse events and no risk of permanent laser scarring of the retina, and the aforementioned discussion, using ivB in treatment for persisting DME appears to be evidence based, and relatively safe practice.

Conclusion

The BOLT Study assessed the safety and efficacy of ivB in persistent DME despite previous laser therapy. The power of the study was 0.8 enabling it to detect BCVA differences between two groups. In line with many other previous studies evaluating ivB’s efficacy, the results indicate significant improvement in the mean ETDRS BCVA, and no significant differences in severe systemic/ocular adverse events compared to the laser group. This study supports the use of ivB in patients with CSME, with adequate precision. However the magnitude of the effect on changes in the severity of diabetic retinopathy, in CMT changes and other adverse events, needs to be evaluated further through large prospective RCTs.

Conflict of interest

None declared.

Correspondence

pavani.kurra@gmail.com