Hiv,cancer,heart,swine and other deaedly diseases that can affect man.
Wednesday, September 30, 2009
High prevalence of pre-cancerous anal lesions in women with HIV
HIV-positive women have a high prevalence of pre-cancerous anal lesions, American investigators report in the January 2nd 2009 edition of AIDS. The researchers found that 12% of HIV-positive women had low-grade pre-cancerous lesions and that high-grade lesions were present in 9% of women. Anal infection with human papilloma virus was an important risk factor for the presence of pre-cancerous anal lesions. There is an increased prevalence of anal cancer amongst people with HIV. A history of anal infection with human papilloma virus has been established as an important risk factor for anal cancer. Pre-cancerous lesions, graded according to their severity (low-grade anal intraepithelial neoplasia, and high-grade anal intraepithelial neoplasia), develop before anal cancer. Only a small percentage of high-grade lesions progress and become anal cancer, and pre-cancerous and cancerous anal lesions can be successfully treated. The sooner such lesions are detected, the higher the chance of treatment being successful. Most of the studies into anal cancer and pre-cancerous anal lesions in HIV-positive individuals have been conducted in gay men. Investigators from the Women’s Interagency HIV Study (WIHS) wished to establish a better understanding of pre-cancerous anal lesions in HIV-positive women and women with a high risk of HIV. They therefore deigned a study to establish the prevalence and risk factors for pre-cancerous anal lesions in these populations. A total of 655 women, 470 of whom were HIV-positive, were recruited included in the investigators analysis. They were evaluated for pre-cancerous anal lesions every six months. Similar proportions of HIV-positive (47%) and HIV-negative (46%) women reported a history of anal intercourse. However, women with HIV were significantly more likely to have abnormal anal cells (31%) when compared to HIV-negative women (9%) (p < 0.003). Furthermore, the investigators found a significantly higher prevalence of anal, cervical and both anal and cervical human papilloma virus in HIV-positive than HIV-negative women (p < 0.001). Low-grade pre-cancerous lesions were detected in 12% of HIV-positive women, but just 1% of HIV-negative women. The investigators then conducted statistical analyses to establish the risk factors for such lesions in women with HIV. In their adjusted analysis that controlled for possible confounding factors, they found that younger age (odds ratio [OR] = 0.59, 95% CI = 0.36-0.97), a history of receptive anal intercourse (OR = 3.2, 95% CI 1.5-6.8), anal infection with strains of human papilloma virus associated with pre-cancerous and cancerous lesions (OR = 11, 95% CI 1.2-103), anal infection with cancer-associated and non-cancer-associated human papilloma virus (OR = 11, 95% CI 1.3-96), and cervical infection with human papilloma virus (both cancer-associated and non-cancer-associated, OR = 3.5, 95% CI 1.1-11). Next the investigators examined the rate of high-grade pre-cancerous anal lesions in the two groups of women. Once again, they found that this was significantly higher (9%) in women with HIV than in HIV-negative women (1%). After controlling for possible confounding factors, the only significant risk factor for this condition in women with HIV was anal infection with human papilloma strains associated with a high-risk of pre-cancerous and cancerous cell changes (OR = 5, 95% CI 0.88-29) and anal infection with human papilloma virus or either a high- and low-risk (OR = 7.6, 95% CI = 1.5-38). “Our findings show that the prevalence of anal intraepithelial neoplasia among HIV-infected women is high and significantly increased above a comparison group of HIV-uninfected women”, write the investigators.
HIV-positive patients with lung cancer have improved prognosis with HIV treatment
HIV-positive patients with non-small-cell lung cancer have a significantly better prognosis if they take HIV treatment, French researchers report in the online edition of the journal Lung Cancer. Patients who took HIV treatment had an average survival of nine months compared to little over four months for individuals who did not take anti-HIV drugs. The life-expectancy of HIV-positive patients has improved dramatically since effective HIV treatment became available. However, several studies have shown that non-HIV-related cancers are an increasingly important cause of illness and death in people with HIV. Earlier research has shown that lung cancer is more common in people with HIV than in the general population. The proportion of people with HIV who smoke is higher than that seen in the general population and this may provide a partial explanation. Studies have suggested that other factors may also explain the higher risk of lung cancer seen in people with HIV, for example chronic lung disease. Few studies have looked at the prognosis of HIV-positive patients with non-small-cell lung cancer, the most common type of lung cancer. French researchers therefore looked at the medical records and outcomes of 49 HIV-positive patients who received treatment and care for this type of lung cancer between 1996 and 2007. They gathered information on factors that could be related to prognosis, such as demographics, smoking, details of the cancer, general health and wellbeing, stage of the cancer, treatment for the cancer, CD4 cell count, viral load, and use of HIV treatment. Most of the patients (42, 86%) were male and Caucasian (46, 94%). All were smokers, and the average duration of smoking was 29 years. The median CD4 cell count was 350 cells/mm3 and median viral load was 1000 copies/ml. HIV treatment was being taken by 36 (73%) when their cancer was diagnosed. Cancer treatment was provided to 43 (88%) patients. The remaining twelve individuals received supportive treatment only. A total of twelve patients underwent surgery. These patients had a median CD4 cell count of 350 cells/mm3 and six had an undetectable viral load. After surgery seven patients were assessed as having stage I (localised) or stage II (localised, but advanced) cancer. Three patients received chemotherapy after their surgery. Ten of the patients who underwent surgery died, seven because of lung cancer. The remaining two patients were still alive without relapse. Chemotherapy was provided to 27 patients with advanced cancer (stage IV, secondary cancers had developed or the malignancy had spread throughout the body). These patients received a median of three cycles of chemotherapy, achieving a partial response or stabilisation of the disease in 40% of patients. The patients were followed for a median of eight months (range, 1-65 months), and 42 individuals died. Lung cancer was recorded as the cause of death in 33 (80%) patients, a non-HIV-related infection in ten patients, and AIDS in one individual. Overall survival time from diagnosis of lung cancer was a little over eight months. The survival rate at one year after diagnosis was 34%, 17% at two years and 7% after five years. In their first set of analysis, the investigators found that the factors associated with improved survival were use of HIV treatment, being completely asymptomatic or able to get on with daily tasks, and weight loss of below 10%. Subsequent analysis that took into account baseline characteristics found that use of HIV treatment reduced the risk of death by 60% (p = 0.027). Patients who were completely asymptomatic (p = 0.0001), or whose cancer was localised or localised and advanced (stage I and II) (p = 0.003) also had an improved prognosis compared to patients with more severe symptoms or advanced cancer. The researchers calculated that patients who received HIV treatment had a median survival time of nine months after diagnosis of their lung cancer compared to 4.5 months for patients who did not take antiretroviral drugs. “To our knowledge, this is the first study demonstrating that HAART [highly active antiretroviral therapy] is a good prognostic factor for survival in HIV infected patients with non-small-cell lung cancer”, write the investigators. They note that HIV treatment has been shown to improve the prognosis of HIV-positive patients diagnosed with other cancers, particularly the AIDS-defining cancers Kaposi’s sarcoma and non-Hodgkin’s lymphoma. Researchers looking at the use of HIV treatment during therapy for other cancers have suggested that the reduced mortality seen in people taking HIV treatment is because this therapy reduces the risk of dying from HIV-related causes. The investigators of the current study do not believe, however that the improved prognosis seen amongst patients who took HIV treatment in their study was due to this factor, noting that there was only one HIV-related death. Other investigators have suggested that HIV treatment by itself may improve survival, or that it improves the immune system’s ability to respond to the cancer. There is a general agreement that HIV treatment and chemotherapy can be combined, despite the possible risk of some overlapping side-effects. The investigators conclude, “for the first time, our study has demonstrated that use of HAART is a good prognostic factor for survival among HIV infected patients with non-small-cell lung cancer”. However, as continuing HIV treatment is essential when providing chemotherapy, the investigators add “it is of critical importance that specialists in infection and oncologists collaborate in making decisions on the choice of treatment associations.”
Incidence increasing of HIV-associated multicentric Castleman's disease, a relatively rare lymphatic cancer
Increasing numbers of cases of the relatively rare lymphatic cancer, multicentric Castleman's disease, are being diagnosed in HIV-positive individuals attending the UK’s largest HIV clinic, according to a presentation to the XVII International AIDS Conference in Mexico City earlier this month by Dr Mark Bower of London’s Chelsea and Westminster Hospital. Castleman’s disease, first described 50 years ago by Dr Benjamin Castleman, is a disorder resulting from over-activity of lymph tissue that can develop into a type of lymphoma. Although rare, it is most often seen in HIV-positive individuals as multicentric Castleman's disease (MCD) which is characterised by swollen lymph nodes, fever, fatigue, weight loss, night sweats, blood disorders and sometimes liver and spleen irregularities. Like Kaposi’s sarcoma (KS), MCD is caused by human herpesvirus-8 (HHV-8). Unlike KS, however, is it very difficult to diagnose and, as Dr Bower revealed during his presentation, MCD is neither associated with a prior AIDS diagnosis, nor are men disproportionately affected. No information exists regarding the incidence and risk factors for MCD in HIV-positive individuals, so these data from the Chelsea and Westminster cohort – which includes 10,997 patients, prospectively followed for over 56,202 patient-years between 1983 and 2007 – provide the first overview of the impact of MCD on HIV-positive people. Since MCD and KS are caused by the same virus, the investigators compared the incidence of both diseases over time. During 25 years of follow-up there were 1180 diagnoses of Kaposi's sarcoma in the Chelsea and Westminster cohort, compared to just 24 cases of multicentric Castleman's disease. This translates to a MCD incidence of 4.3 cases per 10,000 patient-years – about one-fiftieth of KS incidence. However, when incidence was examined during three time periods – the pre-highly active antiretroviral therapy (HAART) era (1983-1996); the early HAART era (1997-2001); and the current HAART era (2002-2007) – incidence of multicentric Castleman's disease was found to have risen progressively, from 0.58 cases per 10,000 patient-years in the pre-HAART era; to 2.8 cases per 10,000 patient-years in the early HAART era; to 8.3 cases per 10,000 patient-years in the current HAART era. Dr Bower conceded that, “there may be some diagnostic ascertainment bias” in the current era, since "we're more familiar with the diagnosis and more likely to make the diagnosis and search for it a bit harder." However, he pointed out, rising MCD incidence in this cohort comes in stark contrast to declining KS incidence over the same three time periods. Multivariate analysis found that unlike the risk of developing KS – which is much greater in men, and much greater with a prior AIDS diagnosis – this was not the case for multicentric Castleman's disease. “There was no gender preference for developing Castleman's disease,” said Dr Bower. The factors that were associated with an increased risk of developing multicentric Castleman's disease included: increasing age; non-Caucasian ethnicity – the risk was higher particularly in black African members of the cohort; a shorter duration since HIV diagnosis; and higher, rather than lower, nadir CD4 cell counts, unlike most HIV-related cancers – one third of MCD patients in the cohort had CD4 counts above 350 cells/mm3. In addition, the analysis found that HIV treatment appears to protect against the development of multicentric Castleman's disease. Although he said that MCD is "a diagnosis that we're going to be making more frequently", Dr Bower pointed out that “the diagnosis is very difficult to make” since clinical and pathological features of MCD overlap with a large number of other illnesses in people who are HIV-positive. Although a lymph node biopsy is the most effective way of establishing a diagnosis, data from the Chelsea and Westminster suggest that measuring HHV-8 plasma viral load may be an important diagnostic tool. In a study of 240 HIV-positive individuals, the vast majority (83%) of those with multicentric Castleman's disease had a detectable HHV-8 viral load at the time of active MCD whereas 65% of those with KS, and 97% of those with lymphoma from other causes had undetectable HHV-8 viral load (p = 0.0001). In addition, individuals with KS with detectable HHV-8 had far lower median viral loads compared with the individuals with multicentric Castleman's disease (3900 vs 41,000 copies/ml). He added that other data suggested that using the HHV-8 viral load may be a helpful marker of MCD activity, since it will fall when the disease goes into remission, and rise again when the disease relapses. However, “as yet,” said Dr Bower, “this is an insufficient assay to make the diagnosis of Castleman's disease, but it certainly seems to help push towards undertaking a biopsy.” Data published in the pre-HAART era suggested that the median survival following a diagnosis of HIV-associated multicentric Castleman's disease was 14 months. However, Dr Bower and colleagues have recently seen long-term remissions with a two-year survival rate of 95% and a five-year survival rate of 67%, following dramatic improvements in treatment that combines chemotherapy and immunotherapy. (Bower 2007) Dr Bower concluded by reiterating that the incidence of multicentric Castleman's disease appears to be rising; and that, unlike KS, the risk of MCD is not associated with the degree of immunosuppression. He added that plasma HHV-8 viral load may be used as a useful diagnostic marker, and that with an aggressive combination of chemotherapy, immunotherapy and splenectomy surgery, where necessary, a five-year survival rate of 67% can be achieved. The British HIV Association (BHIVA) has recently published guidelines in HIV Medicine on the diagnosis and management of HIV-associated malignancies that includes a section on multicentric Castleman's disease. The guidelines can be downloaded from the BHIVA websi
A stronger immune system reduces risk of death from cancer for people with HIV
Researchers with the D:A:D cohort have uncovered another benefit of keeping the immune system strong in people with HIV: a lowered risk of dying from any type of cancer, including both AIDS-related cancers and non-AIDS malignancies. Their report, published in the October 18th issue of AIDS, also found that non-AIDS cancers are accounting for the majority of cancer deaths among people with HIV and are the more common types of cancer among all people with HIV apart those with the weakest immune systems. Thanks to antiretroviral therapy, fewer people with HIV who receive the drugs are dying of AIDS-related causes. Instead, a growing number of deaths are due to non-AIDS conditions, such as cardiovascular disease and cancer. As these non-AIDS conditions become more common, investigators are questioning the impact of HIV, and antiretroviral therapy, on these other conditions. (For an overview, see aidsmap.com’s summary of the 2008 CROI plenary session Morbidity and mortality in the HAART era. Non-AIDS cancers are one class of conditions that have become an important cause of death among people with HIV since the introduction of antiretroviral therapy. There is some evidence that HIV may increase the incidence of some of these cancers, but little is known of factors, including HIV treatment, that influence the risk of cancer death. In this report, investigators turned to the extensive database of the D:A:D cohort to describe the rates of death due to cancer among people with HIV. The D:A:D cohort is an observational study comprising eleven cohorts of patients receiving antiretroviral therapy from three continents and including 23,437 participants. While the primary aim of the cohort is to evaluate the impact of antiretroviral therapy on risk of cardiovascular disease, the cohort collects data on all causes of death, including cancer. From the cohort, the investigators identified 305 patients who died from cancer: 112 died of an AIDS cancer, while 193 died of a non-AIDS cancer. Of the 112 AIDS cancers, 82 were non-Hodgkin's lymphoma, 28, Kaposi’s sarcoma, and two, cervical cancer. The 193 non-AIDS cancer cases included 62 lung cancers, 25 gastrointestinal cancers, 22 haematological cancers, 20 anal cancers, 18 urogenital cancers and 16 liver cancers. The overall death rate for AIDS cancers was 1.1/1000 per years of follow up (95% CI, 0.9 – 1.2) and for non-AIDS cancers, 1.8 (1.5 – 2.1). When investigators assessed death rates at different CD4 cell counts, they found that only when the latest CD4 cell count prior to death were below 50 cells/mm3 were death rates due to AIDS-defining cancers higher than rates due to non-AIDS cancers (20.1 for AIDS cancers versus 6.0 for non-AIDS cancers). Among those with intact immune systems (last CD4 cell count prior to death above 500 cells/mm3), the death rate for AIDS cancers was 0.1 and for non-AIDS cancers, 0.6. Latest CD4 cell count was strongly associated with risk for AIDS cancer death and non-AIDS cancer death. A doubling of CD4 cell count was associated with a halving of AIDS cancer deaths (adjusted rate ratio 0.53 (0.48 – 0.59) and an almost 40% reduction of non-AIDS cancer deaths (0.61, 0.57 – 0.66). Latest viral load measures were not strongly linked to death by either AIDS or non-AIDS cancer. Factors associated with risk of AIDS cancer death were being homosexual, being older, having a previous AIDS diagnosis and being from early in the study cohort. Among the people who received HIV treatment, the investigators noted that those with a low current CD4 cell count but a high nadir count were particularly susceptible to AIDS cancer death, “suggesting that those at highest risk were those whose CD4 cell count had remained low on [antiretroviral therapy], or whose count had risen but subsequently fallen.” When investigators turned their attention to non-AIDS cancer deaths, they found that being older was associated with higher risk, while having joined the cohort more recently was associated with lower risk. Unsurprisingly, non-AIDS cancer deaths due to lung cancer and liver cancer were linked to smoking and active hepatitis B virus infection, respectively. There was not an association between liver cancer and hepatitis C virus infection, though the investigators note that in the cohort, people co-infected with HIV and hepatitis C virus more often die of liver failure than liver cancer. Unexpectedly, AIDS cancer deaths were not associated with HIV treatment use in adjusted analyses, while non-AIDS cancer deaths were. Compared with people who had taken antiretroviral therapy for less than four years, the rate of death due to non-AIDS cancers was 62% lower among people who had never taken HIV treatment and 76% higher among people who had taken antiretroviral therapy for more than four years. One interpretation is that people on HIV treatment are less likely to die of AIDS cancers and thus may be more likely to die from non-AIDS cancers. However, the investigators argue that “A more likely explanation is that after diagnosis of a [non-AIDS cancer], [antiretroviral therapy] may be started quickly to enhance the immune system in preparation for the detrimental effects of antineoplastic drugs. In contrast, patients dying from [an AIDS-related cancer] may be more likely to have stopped or never received [antiretroviral therapy].” The investigators also highlighted the finding that for a similar CD4 cell count, being older was a risk factor for dying from either an AIDS cancer or a non-AIDS cancer. Though this may simply be due to the fact that cancer occurs more frequently in older people, the investigators hypothesise that with age the immune system degrades in ways not captured by CD4 cell counts. While the study did not investigate the impact of antiretroviral therapy directly on risk of cancer death, the investigators conclude that “improvements to patients’ immune systems following the use of [antiretroviral therapy] may be expected to have a positive impact on the risk of death from [non-AIDS cancer], underlining the importance of HIV treatment strategies that aim to prevent immunodeficiency.”
Risk of cancers with infectious cause going down in people with HIV
A large study of HIV-positive people in the US, followed for an average of four years, shows that people with HIV have an approximately sixfold greater risk of developing a non-AIDS-defining cancer with an infectious cause compared to HIV-negative people, with the majority of these cancers potentially related to human papilloma virus (HPV). The findings, from the Kaiser Permanente healthcare database in California, were presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, Canada. Nevertheless the study found that for people with HIV, the risk of developing a non-AIDS-defining cancer with an infectious cause has declined since the introduction of antiretroviral therapy, whereas it has remained constant in HIV-uninfected people since 1996. Non-AIDS-defining cancers are becoming more common as the population of people with HIV lives longer and ages. Some non-AIDS-defining cancers, such as lung cancer, occur more frequently in people with HIV than in the general population, and a recent US study showed that nine non-AIDS-defining cancers occurred more frequently in people with HIV than in the general US population. However, it is not clear if the risk of developing such cancers is increasing, or diminishing due to the effects of antiretroviral therapy. The analysis reported today looked at the incidence of cancers in HIV-positive people receiving care through the Kaiser Permanente managed healthcare programme, which provides care for around one in four Californians. The researchers identified 18,890 HIV-positive patients and 189,804 HIV-negative patients. Information on cancers was collected from the Kaiser Permanente’s cancer registry, and cancers were grouped as infection-related or unrelated. Infection-related cancers were considered to be those of the head, neck, liver, anus, and cervix, as well as Hodgkin’s lymphoma. (However, it should be noted that the vast majority of head and neck cancers are caused by smoking or alcohol consumption; Epstein-Barr virus and human papilloma virus are thought to have a less significant role in the development of these cancers). There were 480 non-AIDS-defining cancers in HIV-positive people: 220 were infection-related and 269 non-infection-related. In HIV-negative people there were 3065 non-AIDS-defining cancers: 398 infection-related and 2698 non-infection-related. The relative risk of the two types of cancers between HIV-positive and HIV-negative people was as follows: Infection-related: 29.7 per 10,000 person-years in people with HIV, 4.4 per 10,000 person-years in HIV-uninfected people (relative risk 6.8, p< 0.001).However, the risk of developing an infection-related cancer fell by around 4% per year during the period under study (1996-2006). Infection-unrelated: 36.4 in people with HIV vs 30.6 in people without (relative risk 1.2, p = 0.002). When the relative risk was compared over three time periods (1996-1999, 2000-2003, 2004-2006) the difference was only significant in the 2004-2006 period (RR1.3, p = 0.002).The most pronounced differences for infection-related cancers occurred in: Anal cancer (80-fold higher risk in HIV-positive people) Hodgkin’s lymphoma (19-fold higher risk) Liver cancer (2.7-fold higher risk)There was no significant change in the risk of Hodgkin’s lymphoma, liver cancer or oropharyngeal cancers over time, but there was a 6% annual decline in the risk of anal cancer (P<0.05). For infection-unrelated cancers, HIV-positive people were found to have a higher risk of: Kidney Lung Melanoma Prostate cancerThere was also a suggestion of an increased risk of colorectal cancer in recent years, Dr Silverberg said. He noted that the findings have limited generalisability to women and the uninsured, due to the fact that while the cohort reflects the epidemiology of HIV in California quite closely, 74% of identified cases were in men who have sex with men.
Incidence of Kaposi’s sarcoma rising among black South Africans
The incidence of Kaposi's sarcoma is increasing amongst Black South Africans and is a growing health problem that requires urgent attention, according to work published by the University of KwaZulu-Natal at the Fourth South African AIDS Conference in Durban. Kaposi's sarcoma (KS) is a rare cancer that is much more common in people with immunosuppression, such as those with advanced HIV infection. The condition, which is characterized in its early stages by dark skin lesions and subsequently by lesions in the mucous membranes, the lungs, the gut and the lymph nodes, is caused by infection with human herpes virus 8 (HHV-8). Despite the association between HIV infection and KS, there is still no well established incidence estimate for AIDS-associated KS in South Africa. The current study, which attempted to estimate this incidence, made use of anonymous administrative records for patients receiving care for KS in KwaZulu-Natal between 1983 and 2006 in public-sector oncology clinics. Age-standardised incidence rates were calculated using provincial census data for the local population in the years of 1985, 1996, 2001 and 2005. Age-specific rates, which were subject to different data constraints, were assessed for the years 1983 to 1989 (the baseline) and for 2006 (the generalised HIV epidemic). The researchers report that age-standardised incidence rates (per 100,000 people) increased from 1.04 to 19.7 between 1983 and 2007. This compares with a standardised incidence ratio in a Ugandan HIV-positive population of 6.7 when compared to the general population. More worryingly, the incidence rate for women during the same period increased fifty-fold, from 0.21 to 11.51. Gender-averaged figures pointed towards an incidence increase from 0.52 to 14.76. Furthermore, the age of peak incidence (the age group in which KS is most likely to occur) was shown to shift from a 55 to 60-year age bracket to a 40 to 50-year age bracket for both men and women. This was expected because HIV is more prevalent in young people than old people. The authors stress that only public-sector patients were considered in the study. Many cases of early and late stage KS may very well have been treated by private doctors or left untreated and, if this was a common occurrence, may very well have contributed to a serious underestimation of KS incidence. The study illustrates the alarming growth of KS as a health problem in rural South Africa. The researchers call for more resources to be directed at quantifying the problem and for better medical resources to be made available for KS sufferers. Our newsletter HIV & AIDS Treatment in Practice published a clinical review of Kaposi’s sarcoma management in resource-limited settings in February 2008.
Ongoing viral replication during HIV treatment associated with lymphoma risk
Ongoing HIV replication when a person is receiving antiretroviral treatment increases the risk of AIDS-related lymphomas developing, German investigators report in the July 1st edition of the Journal of Infectious Diseses. The researchers found that the longer a patient had a detectable viral load, the greater the risk of lymphoma. “To our knowledge”, write the investigators, “this is the first study to show that uncontrolled HIV replication during HAART [highly active antiretroviral therapy], as assessed by cumulative HIV viremia, is predictive of the development of AIDS-related lymphoma”. An accompanying editorial suggests that the findings of the study raise “many questions about the optimal care of HIV-infected patients.” The incidence of AIDS-defining illnesses fell dramatically after the introduction of effective antiretroviral therapy in the mid 1990s. AIDS-related lymphomas are the most common cancer seen in HIV-positive patients and account for approximately 30% of deaths in this population Some earlier research has suggested that HIV replication may influence the development of lymphomas. This is possibly because of ongoing immune stimulation and B cell stimulation. An undetectable viral load is the goal of HIV treatment and has been shown to be protective against the development of lymphomas. However, little is known about the risk of lymphomas for the substantial minority of patients who have ongoing viral replication when taking antiretroviral therapy. Researchers from the German Clinical Surveillance of HIV Disease study therefore looked at the risk factor for the development of AIDS-related lymphomas amongst a cohort of 6022 patients who were taking HIV treatment. A total of 66 AIDS-defining lymphomas were diagnosed in these patients during a total of 27,812 person-years of follow up. Study data were gathered between 1999 and 2oo6. The incidence of any lymphoma developing was 2.4 per 1000 person-years of follow up. Patients who developed a lymphoma had significantly lower CD4 cell counts when HIV therapy was started than patients who remained lymphoma free (90 cells/mm3 vs. 204 cells/mm3, p < 0.01). Furthermore, lymphoma patients also had a significantly higher viral load at the initiation of antiretroviral therapy (126,000 copies/ml vs. 63,000 copies/ml, p = 0.01). The investigators then conducted statistical analysis to identify the factors independently associated with the risk of developing an AIDS-related lymphoma. Multivariate analysis, which controlled for possible confounding factors, showed that increasing age (p = 0.001), a CD4 cell count below 350 cells/mm3 (p < 0.001), cumulative viral load (hazard ratio per 2000 days x viral load log/ml = 1.67, 95% CI; 12.7-2.20, p < 0.001). Next the investigators looked at the risk factors associated with individual types of lymphoma. Risk factors for the development of non-Burkitt high-grade lymphoma were time receiving HIV treatment, a CD4 cell count below 350 cells/mm3 and cumulative viral load during antiretroviral therapy (p = 0.003). Cumulative viral load was the only factor significantly associated with Burkitt-type lymphoma (p < 0.001). There was no association between viral load and the development of primary lymphomas of the central nervous system, the only significant factors being age (p = 0.04) and a CD4 cell count below 200 cells/mm3 (p = 0.015). Cumulative viral load was not a risk factor for the development of oesophageal thrush, an AIDS-defining illness. However, duration of HIV treatment, a CD4 cell count below 350 cells/mm3 and a viral load above 500 copies/ml at the time this condition was diagnosed were all identified as risks. “The present study provides evidence supporting the strong influence of HIV replication on lymphomagenesis”, write the investigators. “Cumulative HIV viremia (rather than the latest viral load) best predicted the development of lymphoma, suggesting an important effect of sustained viremia over time and a distinct pathogenesis of AIDS-related lymphoma, compared with other opportunistic diseases.” Monitoring viral load is a fundamental part of HIV care, and ongoing HIV replication during antiretroviral therapy usually triggers further investigative tests and a change in treatment. The investigators believe that the findings of their study provide an additional reason for doctors to take a detectable viral load very seriously in patients taking HIV treatment. They conclude: “these results should encourage physicians to optimize HAART for patients with persisting HIV replication, in an attempt to achieve complete viral suppression and to minimize the risk of this life-threatening complication.” An accompanying editorial notes that the findings of the German research accord with those of the SMART study. This showed that ongoing HIV replication at any CD4 cell count increased the risk of opportunistic diseases. However, the author notes that the German investigators did not explore the association between viral load and lymphoma risk in patients not taking HIV treatment. She suggests that a fall in CD4 cell count may allows continuing HIV replication to become a significant risk factor for lymphoma. Noting that many patients only find out that they have HIV when their CD4 cell count is so low that they are at risk of opportunistic infections, the author concludes, “continued attempts to encourage earlier diagnosis of HIV infection may at least permit individuals to start receiving HAART before their CD4 cell count decreases to levels that place them at risk for lymphoma.”
Over a third of gay men infected with strain of HPV most associated with anal cancer
Anal infection with human papilloma virus (HPV) is at near universal levels in gay men, a study conducted in Australia and published in the online edition of Sexually Transmitted Infections has found. Significant numbers of men were infected with strains of the virus that carry a high risk of cancerous and pre-cancerous cell changes in the anus. The investigators also found that levels of human papilloma virus infection were particularly high in HIV-positive gay men, who were also more likely to be infected with multiple strains of HPV. Although rare, rates of anal cancer are higher amongst gay man, particularly those with HIV, than in the general population. Infection with certain strains of human papilloma virus, particularly HPV-16, have been strongly linked to the development of anal cancer. However, there is little information on the prevalence of strains of anal HPV infection in gay men. Researchers in Sydney, Australia, therefore conducted a study involving both HIV-positive and HIV-negative gay men who were recruited from the community. A total of 127 HIV-positive and 204 HIV-negative men were included in the study and all had anal swabs. These were analysed in the laboratory using two testing methods to determine the prevalence of human papilloma virus, to determine the virus’s DNA, and to see which strains of the virus were present. Anal HPV infection was found in 79% of men overall. The prevalence was significantly higher in HIV-positive men (94%) than HIV-negative men (70%, p < 0.0001). A majority of men were infected with strains of human papilloma virus considered high risk for the development of pre-cancerous and cancerous cell changes in the anus. The prevalence of such strains was significantly higher in HIV-positive men than HIV-negative men (88% vs 56%, p < 0.0001). The risk of infection with human papilloma virus was not affected by age. Nor was there any difference in prevalence of infection amongst HIV-positive gay men with CD4 cell counts above or below 350 cells/mm3. In HIV-positive men, the only factor significantly associated with the detection of anal infection with high-risk strains of HPV was anal bleeding in the previous twelve months (odds ratio [OR] 8.36, 95% confidence interval [CI] 1.05 to 66.0). However, the investigators’ first set of statistical analysis found that there were multiple risk factors for anal infection with high-risk strains in HIV-negative men. These included a history of anal warts, anal infection with gonorrhoea or chlamydia in the previous twelve months, infection with herpex simplex virus-2, and more than 500 lifetime sexual partners. But subsequent multivariate analysis that controlled for potential confounding factors showed that only a history of anal warts was significant (OR 3, 95% CI 1.30 to 6.81). The samples from 93 HIV-negative men and 36 HIV-positive men were further analysed using tests to study the DNA of human papilloma virus and its strain or genotype. The prevalence of infection with strains of human papilloma virus with a low risk of cancer was similar between HIV-positive (89%) and HIV-negative (87%) men. However, significantly more HIV-positive men (94%) than HIV-negative men (73%) had infection with high-risk strains. Of the high risk strains, HPV-16 was found in 36% of HIV-positive men and 27% of HIV-negative men. More than one strain of human papilloma virus was found in 86% of men. The mean number of strains present in HIV-positive men was seven, versus a mean of four strains in HIV-negative men. “In this community-based population of sexually active homosexual men, anal human papilloma infection was near universal,” comment the investigators. They add, “A wide variety of…genotypes was detected, and co-infection with multiple genotypes was common. An alarming one-third of participants tested positive for HPV-16, the primary causal agent of anal cancer.” The investigators call for larger studies “to asses the natural history of anal human papilloma virus infection in homosexual men. The utility of currently available human papilloma virus vaccines would be informed by further population-based data on the human papilloma virus types isolated from anal cancers in homosexual men.”
Immune suppression has important role in development of non-AIDS cancers
Immune suppression plays an important part in the development of non-AIDS-defining cancers in people with HIV, Australian investigators argue in a letter published in the June 1st edition of AIDS. The investigators were prompted to write to the journal after the publication of a US study earlier this year that found that neither CD4 cell count nor use of antiretroviral therapy were risk factors for such cancers. The authors note that this study, which involved 4500 individuals diagnosed with HIV between 1984 and 2006, did not include an analysis of the impact of the cumulative duration of immune suppression on cancer risk. Furthermore, they refer to the findings of other research that shows a clear link between the risk of non-AIDS-defining cancers and immune suppression. The D:A:D study examined risk factors for death due to cancer in 23,500 patients taking antiretroviral therapy. Among the risk factors for death from a non-AIDS-defining cancer were latest CD4 cell count. Univariate analysis of the results of this study also showed that the cumulative duration of immune suppression, defined as time spent with a CD4 cell count below 200 cells/mm3 was also significant. Research conducted by investigators at the Chelsea and Westminster Hospital in London also showed that a lowest ever CD4 cell count below 200 cells/mm3 and use of antiretroviral therapy were risk factors for the development of a non-AIDS-defining cancer. This research involved over 11,000 patients who attended the hospital between 1983 and 2007. “We believe that the findings from these studies suggest that HIV-related immunosuppression does play an important role in the risk of specific cancers in the HAART era”, comment the authors. They also note “the remarkable similarity in the range of cancers occurring at excess rates in solid organ transplant recipients and people with HIV infection strongly supports an effect of long-term immunosuppression on cancer incidence.” Accordingly, the authors recommend that future large cohort studies should examine “the independent effects of ageing, the time-dependent severity of immunosuppression, and the cumulative duration of immunosuppression on cancer risk.” They also recommend that the role of these factors in the development of individual cancers, or groups of cancers, such as those caused by the same virus, should be examined. They believe that such analyses “will assist in the development of strategies to minimize or prevent the occurrence of cancer in patients with long-term immune deficiency.”
Good survival for HIV patients diagnosed with non-Hodgkin's lymphoma
Two-thirds of HIV-positive individuals with non-Hodgkin’s lymphoma are alive a year after its diagnosis, European investigators report in a study published in the online edition of AIDS. A low nadir CD4 cell count was associated with poorer survival. Nevertheless, the investigators found that in the era of combination antiretroviral therapy, over 50% of HIV-positive patients diagnosed with a lymphoma were alive five years later. “Our results thus support the notion that the gap in survival between non-Hodgkin’s lymphoma patients with and without HIV is closing”, comment the investigators. Non-Hodgkin’s lymphoma is an AIDS-defining cancer and an important cause of death in patients with HIV. Since the introduction of effective HIV treatment, there has been a fall in the number of new cases of this cancer in people with HIV, and an improvement in the prognosis of patients in whom it is diagnosed. Some earlier research has found that a number of HIV-related factors influence the prognosis of patients who develop lymphoma in the era of HIV treatment. These include a low CD4 cell count, a high viral load, and a history of previous AIDS-defining illnesses. Prognostic factors important in the course of the disease in HIV-negative patients, such as age, have also been shown to affect the outcome of HIV-positive patients. In order to obtain a better understanding of prognosis of HIV-positive patients who develop non-Hodgkin’s lymphoma and the factors associated with this, researchers from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group conducted a study involving patients from 33 cohort studies. A total of 67,659 patients were included in the investigators’ analysis and 847 of these individuals developed non-Hodgkin’s lymphoma. All were diagnosed with the cancer after January 1998, and none had experience of HIV treatment before that date. Of these patients, 10% were diagnosed with a primary lymphoma of the brain and 10% with Burkitt’s lymphoma. The investigators divided the patients into three groups according to their experience of HIV treatment at the time this cancer was diagnosed: no HIV treatment; HIV treatment for under 90 days; HIV treatment for over 90 days. Overall, the patients had a median age of 41 years and 82% were men. Non-Hodgkin’s lymphoma was diagnosed in 43% of patients before they started HIV treatment. Of the patients diagnosed with the cancer when taking HIV therapy, 14% had been taking this treatment for less than 90 days. Median CD4 cell count at the time non-Hodgkin’s lymphoma was diagnosed was low at only 114 cells/mm3. This was accompanied by a high viral load (median, 181,000 copies/ml). Viral load was, however, lower in patients who were taking HIV treatment (less than 90 days, 126,000 copies/ml; over 90 days, 121 copies/ml). Of the 763 patients with systemic non-Hodgkin’s lymphoma, 283 (37%) died. The proportion surviving one year was 66%, with 54% alive five years after their cancer was diagnosed. A total of 38 of the 84 patients (45%) diagnosed with primary lymphoma of the brain died. The proportion surviving one year was 54%; however, data were too scarce to estimate five-year survival. Statistical analysis showed that a lowest ever CD4 cell count below 25 cell/mm3 was significantly associated with a poorer prognosis (adjusted hazard ratio [AHR] = 1.64; 95% CI, 1.18 to 2.29). Older age at the time of diagnosis was also associated with poorer survival, as was injection drug use (AHR = 1.55; 95% CI, 1.08 to 2.21). Diagnosis with primary lymphoma of the brain was also associated with poorer survival (AHR = 1.50; 95% CI, 1.01 to 2.23). The investigators also found patients who had been taking HIV treatment for over 90 days at the time their lymphoma was diagnosed had a poorer outcome (AHR = 2.02; 95% CI, 1.56 to 2.61). The authors suggest that lymphomas that develop after HIV therapy has been started are likely to be more aggressive. For example, patients who develop the aggressive Burkitt’s lymphoma often have a CD4 cell count in the region of 200 cells/mm3. “In the era of combination antiretroviral therapy two-thirds of patients diagnosed with HIV-associated systemic non-Hodgkin’s lymphoma survive for longer than 1 year after diagnosis,” conclude the investigators adding, “more advanced immunodeficiency is the dominant risk factor for death in patients with HIV-associated non-Hodgkin’s lymphoma.”
Infections and smoking increase risk of non-AIDS cancers for people with HIV
A meta-analysis has found that, compared to the general population, HIV-positive individuals have an increased risk of several non-AIDS-defining cancers. The research, which is published in the online edition of the Journal of Acquired Immune Deficiency Syndromes, showed that HIV-positive individuals had an increased risk of several infection-related cancers, as well as malignancies that are related to smoking. However, the authors were unable to say if HIV per se increased the risk of such cancers, or if “confounding by unadjusted cancer risk factors may be responsible for the apparent elevated incidence”. Cervical cancer, Kaposi’s sarcoma and non-Hodgkin’s lymphoma are all AIDS-defining cancers. Research suggests that people with HIV may also have an increased risk of developing several other cancers. A previous meta-analysis of seven studies showed that these cancers were often related to viral infections. US investigators have now conducted a further meta-analysis including six additional studies. The investigators stratified their results to see if gender, a previous AIDS diagnosis and antiretroviral exposure affected the risk of non-AIDS-defining cancers. Over one million person years of follow-up were available for analysis. The standardised incidence ratio (SIR) for 34 separate cancers was compared between individuals with HIV and HIV-negative individuals. A total of 4797 non-AIDS-defining cancers were diagnosed in the studies, which were conducted between 1981 and 2007. The most frequently observed non-AIDS-defining cancers were lung cancer (847 cases), Hodgkin’s lymphoma (643 cases) and anal cancer (254 cases). All but two non-AIDS-defining cancers (breast cancer and prostate cancer) were more common amongst individuals with HIV than HIV-negative individuals. This was especially the case with cancers linked to infections such as anal cancers (SIR = 28), liver cancer (SIR = 5.6), and Hodgkin's lymphoma (SIR = 11). The incidence of some cancers associated with cigarette smoking was also elevated amongst people with HIV, including lung cancer (SIR = 2.6), kidney cancer (SIR = 1.7) and laryngeal cancer (SIR = 1.5). Overall, people with HIV were twice as likely to develop a non-AIDS-defining cancer (SIR = 2) than the general population. HIV-positive men had a greater risk of non-AIDS-defining cancers than HIV-positive women (SIR = 1.59). However, the risk varied by cancer type with women having an increased risk of several cancers including those of the kidney and larynx, as well as leukaemia and multiple myeloma. The risk of non-AIDS-defining cancers was higher for patients with an AIDS diagnosis than those who had not progressed to AIDS (all non-AIDS malignancies, SIR = 3.17). There was a modest fall in the incidence of non-AIDS-related cancers in the period after effective HIV treatment was introduced. “HIV-infected individuals had twice the risk of a non-AIDS cancer than the general population”, write the investigators. They note that many of the cancers were related to viral infections. These include human papillomavirus and anal cancer, hepatitis B and C and liver cancer, and Epstein Barr virus and Hodgkin’s lymphoma. “Decreased immune function paired with increased incidence of these infections may be responsible for the increased rates of virally associated cancers among people with HIV”, comment the authors. Cigarette smoking also appears to have been the underlying cause of many of the cancers, especially for women. Reduced hormone levels due to HIV could, the investigators suggest, explain why rates of breast and prostate cancer were lower amongst people with HIV than in the general population. But they also caution “the decreased incidence of these cancers among HIV-infected individuals may also be due to differential screening by HIV status.” The investigators conclude, “this study found an increased SIR for many types of non-AIDS cancers.” However, “it remains unclear whether HIV-infected individuals are truly at a greater risk of non-AIDS-defining cancers, or if confounding by unadjusted cancer risk factors may be responsible for the apparent elevated increase.”
