HIV/AIDS patients continue to battle cancers in the ART era

Lymphomas, other AIDS-defining cancers remain relatively stable as non-AIDS-defining cancers rise.

As patients with HIV/AIDS live longer because of the advent of antiretroviral therapy, physicians treating these patients are helping them face other health challenges as well – illnesses similar to cancer that plague the general population.

Although initial reports noted dramatic decreases of AIDS-defining cancers such as lymphoma in the 1990s after highly active antiretroviral therapy introduction (HAART), recent evidence indicates that lymphoma rates are now holding steady in the population with HIV/AIDS, and non-AIDS-defining cancers may actually be on the rise in this population.

The challenge has become one of sorting out the complications particular to this population of patients. Strategies for prevention and treatment of cancer in patients with HIV/AIDS are largely similar to those for the general population, but there are specific nuances in drug administration and understanding the effect of immune deficiencies that can make managing these patients more challenging. Research presented recently at the 18th International AIDS Conference is shedding new light on these issues.

“Some very important and interesting research questions are being asked right now,” said Paul Volberding, MD, an Infectious Disease News editorial board member. “These can shed light both on immunology and pathogenesis of cancers that we are going to be thinking about for quite some time. It is exciting to watch.”

Volberding said that the questions being raised include why HAART is relatively effective in reducing Kaposi’s sarcoma but not so effective in lymphomas and even less effective in combating non-AIDS-defining cancers such as anal, liver and lung cancers.

“The National Cancer Institute has been interested in HIV-related cancers for the past several years,” he said. “They have devoted substantial resources to this area. We are getting closer. With some of these trials, we can expect to see clarity pretty soon.”

Shifting epidemiology

Results of one such study were presented at the 18th International AIDS Conference by Eric A. Engels, MD, MPH, a senior investigator at the National Cancer Institute.

The results showed significant increases in non-AIDS-defining cancers among individuals with AIDS in the United States, which the researchers attributed to growth and aging of the population with AIDS. This patient population increased from 93,802 people in 1991 to 399,762 in 2005. In 1991, 8% of those cases were among individuals older than 50; that figure had increased to 29% by 2005.

Engels presented data that showed that AIDS-defining cancers — mainly Kaposi’s sarcoma and non-Hodgkin’s lymphoma — declined from 7,284 cases in 1993 to 1,736 cases in 2005. However, non-AIDS-defining cancers increased from 416 cases in 1991 to 2,437 in 2005. A partial breakdown was as follows:

• Anal cancer: 18 cases in 1991, 358 cases in 2005.
• Prostate cancer: 10 cases in 1991, 123 cases in 2005.
• Lung cancer: 112 cases in 1991, 478 cases in 2005.
• Hodgkin’s lymphoma: 72 cases in 1991, 169 cases in 2005.

“The obvious explanation for this is that there are more people with HIV infection, and these people are getting older,” Engels said. “But when we broke it down further and looked at risk, we saw that risk was also increasing for some cancers.”

Engels noted that HIV causes persistent and unpredictable damage to the immune system, and although ART can elevate certain biomarkers to healthy or normal levels, the restoration is never complete.

Immune disregulation

Alexandra Levine, MD, chief medical officer and deputy director for clinical programs at the comprehensive care center at City of Hope in Philadelphia, said that introduction of HAART dramatically reduced the incidence of other AIDS-defining opportunistic infections such as cryptosporidiosis and Pneumocystis carinii pneumonia, but that the reduction in cancers, particularly lymphomas, was not so remarkable. She said that many different kinds of immune deficiencies are associated with an increased risk for cancer.

“Cancer risk is increased if you have had an organ transplantation, if you have auto-immune disease, Lupus, rheumatoid arthritis,” she said. “If ART can make the immune system better but still not completely normal, then the simple reality of the immunodeficiency itself may allow these cancers to continue to exist.”

Volberding said there is a fairly evident relationship between immune competence and the ability to control some viral coinfection that is associated with Kaposi’s sarcoma.

“Those cancers seem very responsive to the immune restoration you see with ART,” he said. “However, the viral relationship with some cancers, like lymphomas, is not so direct. In some cases, Epstein-Barr virus is involved, in some cases, [human herpes virus 8] is involved. In those cancers, the effect of HAART is less striking.”

Volberding said that with still other cancers such as colon cancer or stomach cancer, it is unknown whether there are any viral coinfections at all, and that a relationship between immune restoration and the appearance of the cancer is not usually observed.

Engels said that persistent damage to the immune system is affecting different cancers in different ways.

“For Kaposi’s sarcoma and non-Hodgkin’s lymphoma, the two most common AIDS-defining cancers, people with HIV still get them, and their risk is still quite a bit higher than for uninfected people,” he said. “That probably reflects that some people are not taking HIV therapy, but even people who are taking therapy and have good responses are not protected.”

Lymphomas

Ariela Noy, MD, of the Memorial Sloan-Kettering Cancer Center, said that it is important to understand that HAART does not eliminate the risk for developing lymphoma, but it improves the prognosis if the patient gets lymphoma.

Lymphomas remain a serious risk that should be on the radar of all clinicians treating patients with HIV, according to Noy. She said that HIV leads to immune dysregulation and the HIV associated infections may further stimulate the immune system.

“These reactive lymphocytes are at risk for developing errors in the DNA, which allows uncontrolled cell proliferation,” she said. “A genetic error may occur that makes these lymphocytes no longer under normal regulatory control, which is a necessary step on the way to becoming a cancer cell.”

Questions about the exact pathogenesis of lymphoma in HIV patients such as these are still unanswered, according to Noy. However, she said that, as with most cancers, the extended life span of individuals with HIV may still be the key contributing factor, and that this factor often is linked to doubled consequences.

“We are starting to see people getting a second lymphoma that is unrelated histopathologically to the first,” she said. “Not a relapse, but a completely different go-round.”

Levine cited data from a cohort of more than 7,300 European AIDS patients published by Mocroft and colleagues in 2000. She said that in 1994, lymphoma comprised about 4% of all initial AIDS-defining diagnoses. By 1998, after the introduction of ART, the number of AIDS cases dramatically decreased, but that the proportion of patients with lymphoma as an AIDS-defining illness was 16%.

“If nothing else, these data should tell us that physicians must be aware that lymphoma did not disappear with the advent of HAART,” she said. “Lymphoma must be still considered in the differential diagnosis of a person with AIDS, even if that person has been on HAART.”

Therapy tolerance

David Straus, MD, an attending physician on the lymphoma service in the department of medicine at Memorial Sloan-Kettering Cancer Center, noted another issue in treating patients who have both cancer and HIV — treatment tolerance.

Straus said that most lymphomas in the HIV setting are aggressive lymphomas that require aggressive treatments.

“We can now put aside the HIV issue and treat the aggressive lymphoma, and the results have improved accordingly,” he said. “High-dose chemotherapy with autologous stem cell support was just not feasible in the era before HAART. It is now feasible. This was unthinkable before.” Noy agreed.

“Original studies in the pre-HAART era showed no point in giving standard chemotherapy,” she said. “They often did worse on standard treatment than people who got palliative doses. As a result, there has been a perpetuation of the myth that we should not treat those patients aggressively. We absolutely should.”

Noy said that even in the relapsed or refractory setting, patients can safely receive secondary therapy. She said that the AIDS Malignancy Consortium (AMC) and Bone Marrow Transplant Clinical Trials Networks are opening a study to show that relapsed or refractory HIV lymphoma can be treated in a large consortium study with high dose therapy and autologous transplant.

“Hopefully, this research will squelch any residual naysayers,” she said. “Though the threat of lymphoma is always present, we are optimistic for people with HIV lymphoma at this point.”

Levine said that 5-year survival rates in patients receiving HAART and a combination therapy involving rituximab, etoposide, doxorubicin, vinristine, cyclophosphamide and prednisolone (R-EPOCH) are in the range of 60% to 70%.

“These rates are essentially cure,” she said. “This is not a 1% cure rate, this is long-term disease-free survival. Complete remission rates after chemotherapy are in the range of about 70%. This is very similar to what has been described in HIV-negative patients. The bottom line is that, with HAART, they can tolerate the same kinds of therapy as non-HIV patients.”

Although patients with HIV are achieving similar results as uninfected individuals, Levine said clinicians must remain aware of their patient’s HIV/AIDS status.

“It appears that patients with AIDS lymphoma are more likely to relapse in the brain than HIV-negative patients,” she said. “Therefore, prophylaxis with chemotherapy into the spinal fluid to prevent relapse in that area is commonly done in AIDS lymphoma and in select circumstances of HIV-negative cases.”

Levine said that patients with HIV/AIDS may get the same core regimen, or same platform, R-EPOCH or rituximab plus cyclophosphamide, doxorubicin, vinristine and prednisolone (R-CHOP), but even if they are getting the same regimen, there are subtleties in the treatment that are different.

Straus agreed. “We are seeing a lot of fine-tuning of treatments of aggressive lymphoma,” he said. He also cited the EPOCH study from AMC. “If nothing else, we are seeing that rituximab is safe and effective, and this is good news.”

Prevention

Engels said it is important to counsel patients about good health practices.

“We need to continue to do more to prevent cancers,” he said. “We have to encourage the same practices we would in non-HIV populations and be aware of the special circumstances of HIV-positive patients.”

Engels said that the prevalence of hepatitis B and C viruses in individuals with HIV puts them at greater risk for liver cancer.

Likewise, the prevalence of human papillomavirus in HIV patients makes anal cancer a serious threat.

“We have screening procedures for these cancers, and we should be utilizing them,” he said. “And of course people with HIV tend to smoke more than people who do not have HIV. Clinicians need to be applying pressure to get them to quit, as this can obviously reduce lung cancer incidence.”

Levine said clinicians who treat cancer patients should be aware of HIV trends and prevalence.

“I have seen patients that you would never expect to have HIV, 60- or 70-year-old men or women,” she said. “They come in with lymphoma, they get an HIV test because they have lymphoma in 2010, in this era of the epidemic. Sure enough, the HIV test is positive.”

Levine said that if a patient has diffuse large b-cell lymphoma or aggressive b-cell lymphoma, that individual must be tested for HIV “because the traditional risk groups do not necessarily prove who may or may not have HIV.”

In the end, what all of this adds up to is that patients with HIV are living longer, and although that often means they are developing cancers, vigilant clinicians can keep even these risks in check.

“When it comes time to quote someone a benefit from therapy, we can often tell them that they can reach their normal life expectancy,” Noy said. “That is very important.” – by Rob Volansky

For more information:

• Engels EA. The burden of cancer among HIV-infected persons in the U.S. population. Presented at: 18th International AIDS Conference; July 18-23, 2010; Vienna.
• Mocroft A. Lancet. 2000;356:291-296.

We are beginning to hear as much about the non-AIDS-defining cancers as we once did about the AIDS-defining cancers, if not more so. However, given the effect of HIV pharmacotherapy and its effect on longevity, and the confounding influence of lifestyle risk factors, it is difficult to gauge if and how our approach to non-AIDS defining cancers should differ from that applied to the general population.

Recognizing the importance of immunocompetence in holding certain infections and related cancers in check (KSHV, EBV, HPV), it is accepted that untreated HIV sero-positivity plays a role in the development of malignancies considered as AIDS defining. The disproportionate prevalence of certain non-AIDS defining cancers among HIV positive individuals is not as well understood. Further investigation is needed to clarify the role of HIV infection in the development of malignancy that is not AIDS defining, particularly anal, liver and lung cancers and Hodgkin’s lymphoma. Two areas that deserve further consideration are the possible effects of HIV on the proliferation of cells independently or in consort with other pathogens, and the potential effects of HIV on immune system surveillance and eradication of dysplastic cells. The extent and complexity of cellular dysregulation that occurs in HIV infection is complicated by treatments that alter biochemical pathways outside those they specifically target. Genetic predisposition and life-style, neither of which are easily controlled in epidemiological studies, further obscure the picture. Hopefully, research with an aging cohort of older individuals with HIV will help us to better understand if, when and how HIV contributes to cancers that are routinely prevalent at various life stages. Untangling this HIV-cancer Gordian Knot will likely require the sustained efforts of many researchers rather than the decided slash of a single investigator.

One thing is clear — as people with HIV live longer, clinicians can expect to see more who develop non-AIDS defining cancers. Some cancers may prove to be stimulated or exacerbated by HIV, others may reflect the higher incidence seen in the general population as it ages. Whether treatment of malignancy suspected of being related to or exacerbated by HIV will differ significantly from approaches in the general population is another unanswered question.

In the world of the clinician, management of HIV infection is multidimensional and complex, made even more challenging with a diagnosis of cancer, regardless of the underlying mechanism. Management will continue to require the collaboration of generalists and, as needed, clinical experts in oncology, HIV care, organ systems related to specific cancers, geriatrics, symptom management and palliative care. Optimal treatment will entail adapting the evidence base from various disciplines to address needs as they arise, tailoring interventions to address the biological, psycho-social and spiritual issues in a comprehensive well coordinated plan of care. Thus, as researchers continue to elucidate causal pathways providing a foundation for enhanced prevention and treatment, clinicians must collaborate, sharing current knowledge and acquired expertise to address the on going real-life challenges to care and quality of life faced by those with both HIV and a cancer.

–Ronald J. Walent, RN, PhD

Assistant adjunct professor, Department of Physiological Nursing,

University of California, San Francisco