Research breakthroughs prompt ‘renaissance’ of collaboration between oncologists, HIV experts

Survival for many patients with HIV who are on appropriate therapy now resembles that of the general population.

However, the incidence of non–AIDS-defining cancers (NADCs) in this population is on the rise, and mortality rates in this aging population with HIV are at an all-time high.

During the pre-antiretroviral therapy era, NADCs accounted for approximately 8% to 38% of all HIV malignancies in resource-rich countries. In the ART era, the percentage has increased to between 50% and 58%.

Some researchers suggest longevity is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain this trend in cancer epidemiology, according to an editorial review by Rubenstein and colleagues published earlier this year in AIDS.

“There has been some discussion about whether HIV itself or ART increases the risk for NADCs. Even if it doesn’t, we are definitely seeing more cancers in our aging HIV patients,” said Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, who is an oncologist by training.

Infectious Disease News spoke with several clinicians and researchers about how the treatment paradigm has changed for patients with HIV and cancer, as well as the renewed sense of collaboration between physicians in both specialties.

“More than ever, there is a need for the re-establishment of a relationship between HIV doctors and oncologists, whether it is because of a research question like [the potential role of] bone marrow transplantation, or simply the possibility of drug interactions between chemotherapy and ART,” said Volberding, director of the AIDS Research Institute at the University of California, San Francisco.

The Berlin patient

In July 2013, researchers from Brigham and Women’s Hospital, Harvard Medical School and Massachusetts General Hospital presented data about two patients with HIV and cancer who underwent hematopoietic stem cell transplantation (HSCT) as part of their treatment for their malignancies.

Eight months after HSCT, no HIV DNA was detected in their blood and rectal tissue. In one patient, the benefit persisted more than 4 years post-transplant.

Once both patients were taken off ART, the virus re-emerged. However, that report — along with another well-publicized case of a patient who received a functional cure for HIV — continues to provide hope for researchers, physicians and patients.

Timothy Ray Brown, known as the “Berlin patient,” was diagnosed with HIV in 2005 and acute myeloid leukemia (AML) in 2006. After his AML relapsed, he underwent HSCT in 2008 in Berlin as part of his cancer treatment.

The donor had a CCR5-delta 32 mutation, which results in a mutated CCR5 gene. Lack of a functional CCR5 gene prevents HIV from entering human cells.

No evidence of HIV viremia was documented within the first 20 months of remission after Brown underwent HSCT, and he has remained off ART since his transplant.

“When he received these donor cells, he essentially became resistant to HIV,” Alexandra M. Levine, MD, MACP, chief medical officer at City of Hope National Medical Center in Duarte, Calif., said during an interview. “This was a remarkably fascinating and important case because it was the first time that HIV was clearly shown to have been cured.”

This case prompted speculation that the same types of approaches used in leukemia treatment might contribute to a breakthrough in treatment of HIV, Volberding said.

“Once HIV is established within the body, it becomes a genetic disease,” Volberding said. “It incorporates its genome into the host’s DNA, and we are having a hard time trying to think of strategies to flush that genome out of the body. Now, we would never put a person without leukemia or lymphoma through this because there are serious complications, including a risk for death, with this type of procedure. However, if a person with HIV also has one of those other conditions, it becomes an exciting opportunity.”

So exciting, in fact, that clinicians are becoming more confident that the approach could produce durable, long-term responses for patients with HIV and cancer, according to Michael S. Saag, MD, Jim Straley chair in AIDS research and director of the Center for AIDS Research at the University of Alabama at Birmingham.

“We can theoretically kill off the cells that are harboring HIV while the tumor is being eradicated, therefore resulting in cure,” Saag said.

A shift toward NDACs

Newer, more effective therapies have extended survival for patients with HIV. They also have dramatically improved outcomes for those with HIV and cancer.

“ART is a groundbreaking shift because it is allowing for a better performance status in these patients, and they are in a better place to tolerate the treatments that are needed to get rid of a cancer or control a cancer,” Erin Reid, MD, associate professor of medicine in the division of hematology and oncology at the University of California, San Diego, said in an interview. “This is obviously the biggest ‘player’ so far.”

Because these patients are living longer, physicians are not only seeing signs of early aging but also higher incidence of NADCs.

“A major issue in the Western world is the increase in NADCs. It has increased so much that it is now seen with greater proportion than AIDS-defining cancers,” Ronald T. Mitsuyasu, MD, director of the Center for Clinical AIDS Research and Education at UCLA, told Infectious Disease News.

About 5,000 cases of cancer develop in patients with HIV each year in the United States. Of them, about 2,000 are AIDS-defining cancers. The other 3,000 cases are NADCs.

“Although we continue to see these cancers occurring in younger people, we are seeing more as the AIDS population ages,” Mitsuyasu said. “As people live longer with their HIV, they are more likely to develop cancers of all types. Clearly, the number of cases are anticipated to increase and — as we continue to get better at keeping people alive with their HIV and through many of the opportunistic infections complications — they are now dying of cancers and other diseases more frequently.”

Saag said he agreed that the primary advance in the treatment of patients with HIV and cancer is the reduced incidence of AIDS-defining cancers, the most common of which are Kaposi’s sarcoma, certain high-grade B-cell lymphomas, invasive cervical cancer and primary central nervous system lymphomas.

“However, we are seeing other types of cancers occurring at earlier in ages [in those with HIV] than we would see in people of age-matched control population,” he said. “The question is: Why? This is where a lot of the research is now — evaluating the epidemiology of cancers that occur in HIV patients, and asking why is this happening and what the mechanisms are. The other corollary to that is the resurgence of interest in studying infectious causes of malignancies, from Epstein-Barr virus-associated lymphomas to HPV-related head and neck cancers, and also lung cancers. This is a brand new association that is just being recognized.”

Lung cancer incidence

Another reason for concern is the increased incidence of lung cancer among patients with HIV, a trend made more alarming because lung cancer rates overall are on the decline in the United States.

There are several explanations for the increased incidence of lung cancer in patients with HIV, according to Derek Raghavan, MD, PhD, FACP, FRACP, a medical oncologist and president of Levine Cancer Institute.

“First, as a social issue, young folks still smoke in many environments and the HIV community is not protected from that,” Raghavan said. “In the gay community, unfortunately, cigarette smoking is still a problem. In some cases, lung cancer occurs in response to radiation or occupational exposure, and people with HIV are not protected from those risks.”

Some studies have shown that those who have HIV are much more likely to be smokers than those who do not, Levine said.

“That is a big risk factor,” she said.

However, it does not appear to be the only factor.

Sigel and colleagues compared lung cancer incidence between patients with HIV and demographically similar individuals without HIV. They accounted for smoking and lung cancer stage at diagnosis.

The results, published in 2012 in the journal AIDS, showed the rate of lung cancer was 204 cases per 100,000 person-years (95% CI, 167-249) in those with HIV vs. 119 cases per 100,000 person-years (95% CI, 110-129) among uninfected individuals. After multivariable adjustment, the researchers reported a 70% increased risk for lung cancer among those with HIV (incidence rate ratio=1.7; 95% CI, 1.5-1.9).

A study by Mani and colleagues published in 2012 in Clinical Lung Cancer showed lung cancer risk is two to four times greater in those with HIV than in the general population, even after adjustments for smoking intensity and duration. Researchers also found lung cancer is typically diagnosed at least a decade earlier among individuals with HIV (mean age, 46 years) compared with the general population.

“There may be an interaction between smoking, lung function and chronic infections in the lung and the eventual development of lung cancer in these patients,” Levine said. “It is extremely important that the HIV-infected population and the doctors who care for them understand the critical importance of stopping smoking in these individuals.”

Anal cancer incidence

Although overall rates for anal cancer are low in the United States — an estimated 6,230 people were diagnosed during 2012 — rates have increased steadily since 1940, and HIV infection was found to significantly influence risk among men in the United States.

Meredith S. Shiels, PhD, MHS, of the infections and immunoepidemiology branch of National Cancer Institute’s division of cancer epidemiology and genetics, and colleagues used data from the HIV/AIDS Cancer Match Study to investigate the effect of HIV on anal cancer incidence. They focused on data from 17 states and metropolitan areas between 1980 and 2005.

The results, published in 2012 in the Journal of the National Cancer Institute, showed researchers identified an estimated 20,533 anal cancer cases, of which 1,665 cases (8.1%) involved patients with HIV.

The percentage of men with anal cancer who also had HIV increased steadily, from 1.1% in the 1980-1984 period to 28.4% in the 2001-2005 period (95% CI, 26.6-29.4). Conversely, the percentage of women with anal cancer who were HIV-positive increased slightly, from 0% in 1980-1984 to 1.2% in 2001-2005 (95% CI, 0.93-1.4).

“A large proportion of US males with anal cancer in recent years, particularly young and black males, were HIV-infected,” Shiels and colleagues wrote. “Measures that would effectively prevent anal cancer in HIV-infected males could markedly reduce anal cancer rates at the population level.”

Screening for HPV-associated anal cancer is widely available, and participation rates are high, Reid said, and that has helped reduce rates for advanced forms of anal cancers.

“The other factor here is aging,” Reid said. “As with lung cancer, as the population ages, the risk for HPV-associated cancers increases.”

Role of INSTIs

Safer, more convenient and better-tolerated ART options have helped extend overall survival and reduce therapy-associated toxicity in most patients with cancer and HIV.

“Before ART, or even when it wasn’t widely available, it was more difficult to get standard chemotherapy regimens into our patients with HIV and cancer because their overall performance status was low,” Reid said. “These patients were weaker going into chemotherapy than maybe another patient with the same type of cancer but no HIV. The overall health and strength in any patient with cancer is a predictor for how well they are going to do, and this can predict overall survival in many types of cancer.”

In the past, chemotherapy drugs lowered blood counts in those with HIV, making them even more vulnerable to infections.

“We obviously think of HIV from the old days when we had patients with severe immune deficiency and their susceptibility to infections was a major challenge when their CD4 counts were low,” Volberding said. “When people with AIDS would get cancer, it would seriously limit our ability to treat their cancer.

“Now, antiretrovirals are so effective that the majority of our patients have almost normal CD4 counts and no additional risks for infectious complications. As long as the oncologist recognizes that the patient is on an ART regimen and makes sure they watch for possible drug interactions, the chemotherapy can be just as successful and aggressive as in anyone else without the virus,” he said.

In a paper presented at the 2013 Interscience Conference on Antimicrobial Agents and Chemotherapy, Torres and colleagues evaluated 134 patients with HIV and cancer who were treated between 2001 and 2011.

All patients received optimized background therapy. In addition, 40% received protease inhibitors, 34% received non-nucleoside reverse transcriptase inhibitors (NNRTIs), 17% received integrase strand-transfer inhibitors (INSTIs) and 11% received other treatment.

Sixty percent of the cancers were hematologic malignancies, most common of which was non-Hodgkin’s lymphoma.

At 6 months, researchers determined efficacy of INSTIs (100%) and NNRTIs (96%) were superior to protease inhibitor-based regimens (62%). In addition, rates of adverse effects were higher in the protease inhibitor group (32%) than the NNRTI (16%) and INSTI (5%) groups (P=.02).

“This is the largest series analyzing different antiretrovirals in HIV-infected patients with cancer,” Torres and colleagues wrote. “Protease inhibitors provide the least favorable combination. NNRTIs and INSTI-based treatments have comparable efficacy, but based on safety, INSTIs appear to be the antiretroviral regimen of choice for patients on chemotherapy and those with hematologic malignancies.”

Late diagnoses

Another challenge is when patients are diagnosed with HIV late in the course of their infection, Mitsuyasu said.

“They will sometimes present with cancer as their initial diagnosis. In this circumstance, it is difficult to treat patients because they have a number of other issues that complicate treatment,” he said. “For example, they are more susceptible to mild effects of chemotherapy and radiation, which means we cannot give as high a dose, which may therefore decrease treatment effectiveness.”

Results of previous studies suggest that patterns of cancer incidence also vary based on timing of ART initiation.

Yanik and colleagues evaluated incidence and timing of cancer diagnoses among 11,485 patients included in eight US clinical HIV cohorts who initiated ART between 1996 and 2011.

The median year of ART initiation was 2004, and median CD4 count was 202 cells/mm³.

The results, published in 2013 in Clinical Infectious Diseases, showed incidence rates for Kaposi’s sarcoma and lymphomas were highest within the first 6 months after ART initiation (P<.001) but plateaued thereafter. However, the incidence of all other cancers combined increased about 7% per year (95% CI, 2-13) — from 416 cases per 100,000 person-years to 615 cases per 100,000 person-years — 1 to 10 years after ART initiation.

Patients with a lower CD4 count at ART initiation were at greater risk for Kaposi’s sarcoma, lymphoma and HPV-associated cancers.

“Our results underscore recommendations for earlier HIV diagnosis, followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care,” Yanik and colleagues wrote.

Relationship rekindled

The strides made in the field of HIV during a relatively short time are a credit to researchers in that field and serve as an example for those in other specialties, Raghavan said.

“I recall being in practice early in the HIV era, and it was a dreadful, frightening and debilitating disease for nearly everyone affected,” he said. “Fortunately, this has improved dramatically, but we should not forget that HIV and its transmission remain important health issues. I also think that the progress illustrates what can happen when adequate funds are released for biomedical support and when the community gets behind the patients and the research community in trying to support clinical trials and basic science research.”

Meanwhile, the correlations between cancer and HIV — regarding risk and treatment effects — make communication between oncologists and infectious disease specialists more essential than ever.

“Working closely with oncologists in the spirit of trying to find a cure for HIV has created a renaissance of sorts of communication and collaboration between HIV providers and oncologists,” Saag said.

Mitsuyasu said he agreed.

“From a patient care standpoint, the communication lines have been improved — mostly because we are seeing more of these patients with HIV and cancer, but also because of the ‘Berlin patient’ case,” Mitsuyasu said. “The cure has caused the HIV community to get more interested in whether chemotherapy and/or transplant may have a bearing on eradication of HIV.” – by Jennifer Southall

References:

Henrich T. Abstract WELBA05. Presented at: Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia.
Mani D. Clin Lung Cancer. 2012;13:6-13.
Palacios J. Int J STD AIDS. 2014;25:239-243.
Rubenstein PG. AIDS. 2014;28:453-465.
Shiels MS. J Natl Cancer Inst. 2012;104:1591-1598.
Sigel K. AIDS. 2012;26:1017-1025.
Torres H. Abstract #H-1255. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 10-13, 2013; Denver.
Yanik EL. Clin Infect Dis. 2013;57:756-764.

For more information:

Alexandra M. Levine, MD, MACP, can be reached at City of Hope National Medical Center, 1500 E. Duarte Road, Needleman #213, Duarte, CA 91010; email: alevine@coh.org.
Ronald T. Mitsuyasu, MD, can be reached at Center for Clinical AIDS Research and Education at UCLA, 1399 S. Roxbury Drive, Suite 100, Los Angeles, CA 90035; email: rmitsuya@mednet.ucla.edu.
Derek Raghavan, MD, PhD, FACP, FRACP, can be reached at Levine Cancer Institute, 1025 Morehead Medical Drive, Charlotte, NC 28204; email: derek.raghavan@carolinashealthcare.org.
Erin Reid, MD, can be reached at Division of Hematology-Oncology, University of California, Moores UCSD Cancer Center, 3855 Health Sciences Drive, MC-0987, La Jolla, CA 92093; email: egreid@ucsd.edu.
Michael S. Saag, MD, can be reached at Center for AIDS Research at the University of Alabama at Birmingham, BBRB 256, 1720 2nd Ave. S, Birmingham, AL 35294-2107; email: msaag@uab.edu.
Paul A. Volberding, MD, can be reached at AIDS Research Institute, UCSF, 50 Beale St., 13th Floor — UCSF Box 0886, San Francisco, CA 94105; email: paul.volberding@ucsf.edu.

Disclosure: Levine, Mitsuyasu, Raghavan, Reid, Saag and Volberding report no relevant financial disclosures.

Should lung cancer screening be mandatory for patients with HIV?

National Lung Screening Trial-eligible individuals with HIV in otherwise good health may be considered for lung cancer screening.

Given the survival benefit demonstrated in the National Lung Screening Trial (NLST), there is increasing agreement that lung cancer screening with low-dose CT should be offered to all persons who meet eligibility criteria for the trial (aged 55 to 74 years, with at least a 30-pack-year smoking history), which does not exclude those with HIV infection.

HIV-positive women and men in otherwise good health could, in theory, benefit from this technology. HIV-infected individuals have a several-fold increased risk for lung cancer relative to the general population, even after accounting for smoking. Thus, screening and early treatment of lung cancer could be of great importance in HIV-positive smokers in the United States, now that through the widespread use of combination antiretroviral therapy, longevity for HIV-infected persons increasingly approximates that in the country as a whole. Until proven otherwise, NLST-eligible populations should not be routinely excluded from potentially life-saving lung cancer detection and treatment.

However, there are a host of issues specific to HIV that will need to be addressed before low-dose CT is widely used to screen for lung cancer in all HIV-positive smokers. In particular, we must be concerned about a potentially higher rate for false-positive screening results — due either to infection from an immunocompromised state or chronic inflammation — that result in unnecessary psychological distress, as well as physical risk from diagnostic interventions. Ninety-one percent of the NLST included whites, whereas the HIV epidemic disproportionately affects minority populations, including immigrants from countries endemic for tuberculosis and fungal infections that may not be readily distinguished from lung cancer by low-dose CT. This is a matter that requires active research.

Conversely, there also is the question of whether the NLST screening criteria are appropriate or too conservative for this population. The published series of HIV-positive lung cancer cases to date have suggested a median age of lung cancer diagnosis in persons with HIV below the age of NLST eligibility (and frequently in the fourth decade of life), suggesting that most HIV-infected patients would not have had opportunity for early lung cancer detection had NLST age criteria been applied. Thus, the proper age and smoking intensity thresholds used to define the screening population will need to be separately addressed for HIV-infected populations.

In summary, NLST-eligible persons with HIV in otherwise good health may be considered for lung cancer screening, bearing in mind the above-mentioned concerns. Although it is premature to recommend low-dose CT in all HIV-positive individuals, the potential benefits are substantial and should be a more active research focus. Answering the important questions above regarding low-dose CT screening in persons with HIV is critical to addressing their high burden for lung cancer, currently responsible for 30% of cancer deaths and 10% of non–HIV-related deaths in this population.

Missak Haigentz Jr., MD, is an associate professor of clinical medicine at Albert Einstein College of Medicine and Montefiore Medical Center, and chair of the AIDS Malignancy Consortium’s Non-AIDS Defining Cancer Working Group. He can be reached at Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461; email: mhaigent@montefiore.org. Disclosure: Haigentz reports no relevant financial disclosures.

More data are needed with regard to lung cancer screening in the HIV-infected population.

Patients with HIV are at increased risk for lung cancer, due to unclear factors associated with chronic HIV infection. It might seem, therefore, that this group should be strongly considered for lung cancer screening.

However, the decision to recommend lung cancer screening to a patient requires careful consideration. The NLST demonstrated that lung cancer screening with low-dose CT scans saved lives among heavy smokers (primarily those without HIV). The balance of harms and benefits, therefore, seems relatively clear in patients who met the enrollment criteria for that trial but do not have HIV.

The safety of lung cancer screening depends heavily on the false-positivity rate of lung cancer screens in a particular group of patients. This is one important reason why more data are needed with regard to lung cancer screening in the HIV-infected population before a strong recommendation is made about screening smokers who are HIV-positive.

The false-positivity rate associated with lung cancer screening with low-dose CT is a critical safety determinant in this screening process. A positive lung cancer screen can lead to highly invasive tests, such as needle or surgical lung biopsy, which can sometimes have serious complications. Patients with HIV are at higher risk for having prior lung infections, which may lead to a higher rate for false-positive lung cancer screens. HIV also is associated with a higher risk for emphysema, which may lead to a greater risk for complications associated with lung biopsy.

These factors suggest that the direct application of NLST data to HIV-infected smokers may not be appropriate. Efforts are currently underway to use simulation modeling to extrapolate NLST data specifically to HIV-infected persons.

Recent preliminary data derived from CT scans in a cohort of asymptomatic HIV-infected and uninfected veterans at risk for lung cancer suggests that HIV-infected smokers with CD4 counts greater than 200 may have a reasonable safety profile for CT-based lung cancer screening (Sigel K. AIDS. 2014;Published online ahead of print Jan. 2). A limitation of this study was that it did not include a formal screening protocol, although several lung cancer screening studies are currently enrolling HIV-positive smokers to specifically evaluate the safety and efficacy of this technology in this population.

Therefore, more data are needed before strong recommendations should be made with regard to lung cancer screening in the setting of HIV.

Keith Sigel, MD, is an assistant professor of medicine in the division of general internal medicine at Mount Sinai School of Medicine. He can be reached at Mount Sinai School of Medicine, 1428 Madison Ave., New York, NY 10029; email: keith.sigel@mssm.edu. Disclosure: Sigel reports no relevant financial disclosures.