AIDS Stages of Care – Three So Far; Will Number Four Come Soon?

It was just 30 years ago in June 1981 when the first cases of what came to be known as Acquired Immune Deficiency Syndrome (AIDS) were published by the Centers for Disease Control (CDC) in its Morbidity and Mortality Weekly Report (MMWR.) These were men who had a wasting illness and died of unusual infections, ones of the types seen mostly in “immunocompromised hosts.” These were infections with which I was very familiar in my work treating and preventing infections in aggressively treated cancer patients at a branch of the National Cancer Institute. They included pneumocystis, cyrptococcus, toxoplasma, candidia, zoster, disseminated herpes simplex and others. They tended to develop in patients who had a type of cancer that suppressed their cellular immune function as in chronic lymphocytic leukemia, lymphoma, Hodgkin’s or after bone marrow transplantation. Some of these same infections occurred in patients who received drugs to prevent rejection after kidney, heart or lung transplants. So it was immediately clear that what would become known as AIDS was a disease that markedly affected the cellular immune function of these patients.

It would be only a few years, 1984, until the causative agent was discovered to be a retrovirus (Dr Robert Gallo and Dr Luc Montaginer) and a test was developed (Gallo) to render the blood supply safe. Meanwhile the initial years of what soon was recognized to be an epidemic were spent treating these opportunistic infections in these patients with a rapidly fatal disease once it was diagnosed as AIDS. In retrospect this was the first stage or phase of disease management; it would evolve over the years.

By 1987 the first of the antiviral drugs zidovudine (or AZT) to actually treat the underlying HIV infection was approved by the FDA after studies began at Burroughs Welcome by David Barry, MD and others and at the National Cancer Institute by Samuel Broder, MD and others. Approval came within 25 months of initial studies; a record at the time. Soon came many other drugs and by 1996 there were multiple active agents which when combined produced HAART or Highly Active Anti Retroviral Therapy. This was a distinct turning point because for the first time this lethal disease became a controllable chronic illness where one could survive for decades or possibly more. But if one stopped the drugs once immune function returned toward normal, the disease rapidly recurred in force. So it was suppressed but definitely not cured. Now the key was to get the drugs to the patient, get good compliance and give careful follow-up. Getting the drugs to the patient is no mean feat since they are inherently expensive and many patients are uninsured or underinsured. Taking multiple drugs many times per day is difficult for anyone but harder still if the person is living in poverty or is homeless or is a child with perhaps drug addicted parents. And careful follow-up is difficult for all of the same reasons plus others. And of course the challenges are perhaps even more difficult in many developing countries where the stigma of AIDS is high and the logistical means of getting both the drug and the caregiver to the patient are immense, yet this is just where the vast majority of infected individuals live.

Now a third stage has evolved. With many patients living very long times, caregivers are witnessing a set of new challenges. These are the consequences of long term chronic illness and long term drug treatment. Many patients develop a unique change in body habitus with loss of fat in the face and limbs but an increase in abdominal adipose tissue deep in and around the viscera. The metabolic syndrome is frequent and it is followed by diabetes in many. And late onset cancers of many types are being increasingly recognized. Early onset coronary artery disease is another manifestation of the changing nature of this disease and its treatment. Some believe that the chronic infection leads to chronic inflammation which in turn drives the intimal development of plaque in the coronary arteries and others like the carotids. Early onset osteoporosis is also common with 50 to 67% having osteoporosis or osteopenia well before the expected age. With continued loss of bone mineral density, the risk of fracture at an earlier age with its attendant implications for loss of mobility, hospitalization and death is high.

So for the physician, the change in these evolving stages has been from spending 90% time managing infections to 90% managing the complexities of therapy, its many complications and the long term complications of the chronic infection. Today, the HIV patient on HAART needs regular evaluations for coronary artery disease, metabolic syndrome and osteopenia with life style adjustments and possibly further drug interventions as preventive measures.

There are over 25 licensed antivirals for HIV infection and more are on the way. But whichever ones are used, they must be continued. Stopping has repeatedly proven to be linked to relapse and earlier death.

What will the forth stage be and when will it begin? Let us hope it is the discovery of a vaccine. Only a vaccine will ultimately drive the epidemic down and possibly even contain or eradicate it the way smallpox was or polio and measles could be. The HIV has proven to be very difficult to conquer with a vaccine. Some of the problems include that the initial infection usually goes unnoticed and then it remains latent for many years until the earliest evidence of AIDS appears. Another is the ubiquity of the virus and its ability to undergo sufficient change to escape immune detection. Once the T cell is infected, it is infected for life so a vaccine must be used before, not after, exposure. Of course, there has never been a vaccine produced before to a retrovirus so this in itself is a new hurdle with limited knowledge from former vaccine research to base today’s work upon. The vaccine must block the virus’ ability to enter the cell suggesting an antibody rather than a cellular immune-based vaccine. Dr Robert Gallo, Director of the Institute of Human Virology - believes the target must be the virus envelope – the “fingers” that attach to the T lymphocyte. He and his colleagues recently received over $24 million from the Gates Foundation and the military to further research in this direction.

With about 2,700,000 new infections per year worldwide, a vaccine cannot come too soon. But even when it does, the logistics of getting it to the world’s neediest will be fraught with difficulties. If getting susceptible children immunized against polio and measles has been difficult, HIV will be much more so.

Improving Cancer Patient Care While Markedly Reducing Costs

It is often difficult to appreciate that improving the care of patients can actually reduce the costs of care. Last year Dr H Brody wrote in the New England Journal of Medicine (vol 362, p283-5) about “Medicine’s ethical responsibility for health care reform – the top five list.” In essence he challenged physicians to be first to find ways to rationally reduce health care costs by identifying the top five tests or treatments in any given specialty or subspecialty that could be markedly reduced or even eliminated without harm to the patient. He made some specific suggestions to get things started.

Now Drs.Thomas Smith and Bruce Hillner, two oncologists from the Massey Cancer Center in Virginia, have accepted the challenge and published in the same journal (vol 364, p21, May 26, 2011) a proposed list of five suggested changes in medical oncologist’s behaviors and five changes in attitudes and practices. Their proposal is noteworthy because it directly addresses some of the most important issues that affect cancer patient care yet inordinately increases the cost of that care.

I will not repeat each of their suggestions but will comment on a few. One change in behavior is to limit chemotherapy to patients with a good performance status (with an exception for those with highly responsive disease.) It is well known that a person’s performance status is a very strong predictor of whether a patient will respond to a treatment or have any meaningful extension of survival. The authors point out that their proposal is in line with current guidelines by national oncology organizations. They make the simple recommendation that a patient should not be given chemotherapy if he or she cannot walk into the clinic unaided. Unfortunately, many oncologists today push ahead with further treatment despite their patient’s performance status.
Another suggestion is to “replace the routine use of white blood cell stimulating factors with a reduction in chemotherapy dose in metastatic solid tumors.” The hematopoietic colony stimulating factors (CSFs) are very valuable in pushing the bone marrow to recover white blood cell numbers after aggressive treatments. The concept is that infection is common when the white blood cell count drops below 500 per ul. This is a common occurrence in the treatment of acute leukemia and some other situations where very aggressive chemotherapy is used and the CSFs can be lifesaving in those patients. But they are not needed for modest reductions in WBC counts. In truth, drops below 500/ul rarely happen in the treatment of patients with most solid tumors such as breast, prostate, lung or colon cancer. Yet these very expensive stimulants are used routinely but at high cost. Smith and Hillner suggest that at about $3500 per injection, the sales by oncologists to their patients’ amount to some $1.25 billion per year.
And there is the rub – to change these two practice patterns would be to substantially reduce the oncologist’s income. Oncologists earn a decent but not high income from basic care of their patients. But fully another one half comes from the administration of chemotherapy and support medications such as drugs for nausea and vomiting and drugs to boost the bone marrow to produce red blood cells (erythropoietin) and white blood cells ( pegfilgrastim, Neulasta). In effect they serve as a pharmacy for these drugs, buying them wholesale from distributors, preparing them and administering them while collecting a markup for their effort. This brings their incomes to among the highest among internists. To cut back on chemotherapy or Neulasta administration would have a telling financial impact.
Another suggestion, this one a change in attitude, is to address the importance of end-of-life discussions. The authors point out the truism that such discussions are a critical perquisite to good care planning by both doctor and patient and family. But they point out that far too often, oncologists wait until new symptoms appear or until they feel there is nothing else that can be done before entering this type of discussion. But when such discussions are held at an appropriate time, there is greater use of hospice and “less depression or anxiety, less aggressive end-of-life care and [patients] rarely die in an intensive care unit or on a ventilator.” Further “it allows the surviving caregiver to have a better quality of life and would save our society millions of dollars.” And yet, such discussions are all too infrequent or come too late. It is the physicians’ obligation to their patients and patients’ families to be honest and direct, albeit caring and compassionate at the same time.

With these changes (and some of the others that Smith and Hillner recommend) in behaviors and attitudes, the care of cancer patients would be greatly improved yet the costs would be very greatly reduced. That is a good exchange. Let’s hope these suggestions become the norm of care and that physicians in other specialties take up Brody’s challenge as effectively.

Using Genomics to Improve Treatment of Lung Cancer

Drug companies can use genomics to create targeted drugs like imatinib (Gleevec) and trastuzumab (Herceptin.) Physicians can then use the results of genomic studies to guide prescribing. As discussed in prior posts, a person with Philadelphia chromosome-positive (i.e., having the BCR-ABL translocation with its aberrant tyrosine kinase) chronic myelocytic leukemia will likely respond to Gleevec. And a woman whose breast cancer shows high levels of the Her2neu receptor will likely respond to Herceptin. There would be no reason to treat a Philadelphia chromosome-negative CML patient with Gleevec nor a breast cancer patient without Her2neu receptors with Herceptin.

Recently the treatment of lung cancer has advanced considerably as a result of genomic analysis of the tumor and the development of targeted drugs. Lung cancer is divided into a number of different categories based on the microscopic appearance under the microscope. One type is called small cell and the others are usually “lumped” together as “non small cell” lung cancer because the former is treated much differently than the latter group. The non small cell lung cancers can be genomically evaluated to determine if there are certain common genetic mutations such as KRAS, EGRF, MEK and other mutations or the EML4-ALK translocation.

Patients with the EML4-ALK translocation respond reasonably well to the tyrosine kinase inhibitor crizotinib (somewhat similar to the one used for CML). As with the translocation seen in CML, this is a fusion gene that occurs during a translocation of two parts of two chromosomes that lead to a portion of the normal EML4 gene being fused next to the normal ALK tyrosine kinase gene. When this happens the new gene transcribes a variant tyrosine kinase protein which leads in part to the development or progression of lung cancer. Studies to date indicate it to occur mostly in the subtype called adenocarcinoma, in those with prior treatment, in younger patients and those who have no or a minimal smoking history. Although this represents just a small subset of all lung cancer patients, treatment of them in a Phase 1 trial with crizotinib resulted in a confirmed response in 57% (47 of 82) of patients with another 33% (27 of 82) having stabilized disease. [Kwak et al, New England Journal of Medicine, Oct 28, 2010] Although not a randomized trial, it is well known that most second line treatment regimens have no better than a 10% response rate so this would appear to be a breakthrough of sorts. Certainly it is not a panacea, nor a cure. But with minimal side effects these patients received some useful benefit and probably will have a lengthened survival Further studies will need to be done but if it is correct that about 5% of lung cancer patients have this fusion gene, then about 9000 patients per year would potentially benefit form crizotinib or similar ALK kinase inhibitors. Concurrently, one would not choose to use this drug in patients without this fusion gene and its abnormal protein. It also appeared that some patients had a further mutation such that crizotinib was not effective in them. [Note: Crizotinib is not yet approved by the FDA so access to the drug is via clinical trials.]

Patients who have the EGRF mutation appear to be distinct from those who do not as to response to the drugs erlotinib (Tarceva) and gefitinib (Iressa). EGRF is a tyrosine kinase that when mutated appears to play a role in lung cancer development and progression. Those who do have this mutated gene and its transcribed protein will respond to these two drugs in about 70% of cases with progression free survival of about a year and total survival of about two years. This would appear to be superior to standard drug therapy used today. Without this mutation, the patient will do much better treated with chemotherapy. So the treatment of a new patient with lung cancer today should include genomic analysis of the tumor so that the patient can receive the most appropriate first line treatment and then reanalysis later to determine if there are further mutations or translocation that would direct second line treatment options.

This is just one more example of how genomics is making medical care more custom-tailored, one of the five key medical megatrends.