Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 3 - May, 1994
Michael A. Poles, M.D., Edward A. Lew, M.D., and Douglas T. Dieterich, M.D.

By age 50, approximately half of the American population has evidence of past CMV infection, but the prevalence appears to be even higher among homosexual men. Most patients who have CMV disease are infected with this virus long before they become HIV infected. CMV is typically contracted in infancy and childhood, but patients may also become infected through sexual contact or after receiving infected blood products. In individuals with intact immune systems, infection usually goes unnoticed or results in a mononucleosis-like illness. After infecting a patient, the virus becomes "latent," hiding in the host's cells. Under conditions of immunosuppression, such as with AIDS, the virus may "reactivate" and cause symptomatic disease. This does not usually occur until a patient's CD4 cells fall below 100, and more typically below 50. CMV infection of the gastrointestinal tract commonly results in inflammation, erosions and ulceration of the mucosal linings. This may be quite destructive, and occasionally leads to damage throughout the entire wall of the gut. It may cause perforation of the gastrointestinal tract. Perforation and obstruction due to CMV is responsible for 33 percent of all surgery required in patients with AIDS.[4]

Esophagitis

Disease of the esophagus is very common in patients with AIDS, and CMV is the responsible agent in ten to 40 percent of cases.[5] Its most common physical symptoms are painful swallowing or the sense of food sticking in the throat. Patients sometimes also complain of chest pain or hiccups. These symptoms may result in decreased food intake in patients with normal appetites, dehydration, weight loss and malnourishment.

The diagnostic procedure of choice for CMV esophagitis is upper endoscopy, in which the physician, usually a gastroenterologist, passes a lighted scope through the mouth into the esophagus. The CMV-infected esophagus often appears inflamed and ulcerated, though CMV infection of the esophagus can occasionally take the form of a mass resembling a cancer. Since other esophageal infections in AIDS patients may manifest themselves in a similar manner, biopsies are taken to confirm the diagnosis.

Colitis

CMV infects the colon, or large intestine, in slightly more patients than it does the esophagus. While there is no typical pattern of gastrointestinal complaints caused by lower CMV gastrointestinal disease, it often is associated with intermittent or persistent diarrhea with cramping, lower abdominal pain, involuntary rectal spasm and weight loss. The stool may be watery, semi-formed or formed, and may be accompanied by bleeding. In some patients, diarrhea can be quite severe, with up to twenty bowel movements each day, resulting in severe loss of fluid and electrolytes from the body. Other patients may have no discernible diarrhea at all. Fevers also are common in patients with CMV colitis.

The diagnostic procedure of choice for CMV disease in this location is, again, endoscopy. In this case, colonoscopy is performed, using a lighted scope passed via the rectum to examine the whole colon. Colonoscopy is performed only after the stool has been examined multiple times for evidence of other pathogens that may be responsible for the symptoms. The colon of patients with CMV colitis appears diffusely inflamed and bleeds easily on contact with the endoscope. Biopsy is necessary to rule out other infectious and noninfectious processes.

Other Gastrointestinal Disease

The stomach is susceptible to the same disease processes as the esophagus, including infection with CMV. CMV gastritis, or inflammation of the stomach, may be asymptomatic, but often results in severe continuous upper abdominal pain, fever, hemorrhage or obstruction. CMV infection of the small intestine may result in similar symptoms as well as weight loss and diarrhea. While CMV may infect any part of the small intestine, it rarely does so without involvement of other gastrointestinal organs.

CMV infection of the liver and pancreas is quite frequently found at autopsy, but does not usually result in clinical problems. Liver infection may result in a hepatitis with fever, right upper abdominal pain, an enlarged liver and abnormal tests of liver function, but rarely is of clinical significance. If CMV hepatitis is suspected in the appropriate clinical picture, such as in patients with the above symptoms and CMV in another organ, we recommend biopsy of the liver through the abdominal wall, although this is controversial.

CMV infection of the biliary tract leading from the liver to the small intestine is more important clinically, causing right-sided abdominal pain, fever, nausea, vomiting and possibly jaundice - a yellowing of the skin due to elevated bile pigments in the blood. It is usually diagnosed endoscopically after discovery of dilated bile ducts on ultrasound examination. Pancreatic CMV disease mostly occurs without noticeable symptoms, but in rare instances may result in pancreatic failure.

Diagnosis

Rapid diagnosis of CMV disease may lead to improved survival. A variety of diagnostic methods have been attempted, but the most useful is microscopic examination of biopsy samples. CMV infection of human cells results in characteristic changes found in these biopsies. CMV-infected cells become enlarged with a so-called "owl's-eye" appearance; they are typically found in areas with considerable inflammation. Special tests, which involve such staining techniques as immunofluoresence and DNA in-situ hybridization may be used by experienced pathologists to confirm the presence of CMV in these cells. Newer procedures, such as polymerase chain reaction (PCR), which identifies minute quantities of CMV DNA in body fluids and tissue samples, may be helpful in the near future.

Culture of CMV from bodily fluids probably adds little diagnostic information. Use of radiographic techniques such as barium exams and CT scans may reveal defects in the esophagus, stomach or intestines. But without biopsy of those lesions, diagnosis is uncertain, and treatment premature.

Treatment

In the absence of therapy, CMV disease is progressive and is associated with a high mortality rate. Early treatment is essential, and may alter the course of CMV disease, including the spread of CMV to other locations in the body. Treatment may also prevent severe consequences of CMV disease such as perforation and hemorrhage, which may result in death. The two most commonly used treatments for CMV infection are ganciclovir (cytovene, made by Syntex Laboratories) and foscarnet (foscavir, made by Astra Pharmaceutical Products). Both are currently approved by the U.S. Food and Drug Administration.

Ganciclovir

Ganciclovir has been shown to be effective in the treatment of both CMV esophagitis and colitis in patients infected with HIV, resulting in increased time until relapse of CMV and increased survival. Ganciclovir results in symptomatic and endoscopic improvement in approximately 80 percent of all patients with CMV esophagitis or colitis.[6] This is about the same response rate as seen in ganciclovir-treated patients with CMV retinitis. Unfortunately, ganciclovir must be given intravenously two times a day during induction, and once daily during maintenance therapy. It causes adverse side effects that lead to discontinuation of therapy in about one- third of patients.

The most common adverse effects are on the bone marrow, resulting in a decrease in the number of neutrophils (a type of white blood cell whose loss predisposes patients to severe bacterial and fungal infections). Ganciclovir may also cause lowering of the platelet count, which can increase the risk of bleeding due to decreased clotting ability of the blood. The risk of toxicity is worsened when ganciclovir is given with AZT (zidovudine), resulting in the need to discontinue the latter agent in a significant percentage of patients. Adverse reactions are decreased when either ddI or ddC are used instead of AZT. Blood counts must be checked two to three times per week during induction and weekly during maintenance, and the dose of ganciclovir decreased if toxicity develops. Other side effects include headaches, confusion, nausea, vomiting, diarrhea and, possibly, testicular damage.

Foscarnet

Foscarnet has also been found to be effective in treating CMV disease, and appears to inhibit HIV as well. It is as effective as ganciclovir in the treatment of CMV gastrointestinal disease and can be used both in the newly infected patient and in patients who have relapsed after therapy with ganciclovir.[6] In one head-to-head trial of patients with CMV retinitis, comparing foscarnet to ganciclovir, the drugs had similar efficacy, but the mortality rate was higher with ganciclovir, possibly due to the anti-HIV effect of foscarnet.[7]

Like ganciclovir, foscarnet is an intravenous medication, but it must be given three times a day during induction and once daily during maintenance therapy. Twice daily induction dosing has been studied, and appears to be as effective as thrice daily dosing. It may significantly improve quality of life and decrease cost of caring for these patients.[8]

Foscarnet has a different side effect profile than ganciclovir. While foscarnet does not affect the bone marrow tissues, and therefore can be used concurrently with AZT, it does have a toxic effect on the kidneys that results in passage of excess electrolytes into the urine. This toxicity can be reduced with vigorous use of saline hydration solutions or by reducing or stopping the medication. Other adverse effects associated with foscarnet include nausea, vomiting, diarrhea, oral and penile ulceration, and seizures.

Standard Treatment Regimens

Treatment usually begins with three weeks of ganciclovir. If there is no elimination of the virus from biopsies taken during repeat endoscopy, or the patient continues to experience severe symptoms, he or she is switched to foscarnet. If there is only a partial response to ganciclovir, the patient can be re-induced with ganciclovir for another three weeks. It may also become necessary to switch between medications when serious toxicity occurs. If there is a response to either agent, maintenance therapy is begun. Both ganciclovir and foscarnet result in suppression of CMV, but not elimination. Maintenance therapy appears to be necessary for the long-term control of symptoms as well as the prevention of CMV dissemination to other sites. Maintenance therapy is controversial for CMV gastrointestinal disease, though, as opposed to CMV retinitis. Progression during maintenance therapy will require re-induction. If both medications fail to result in improvement of gastrointestinal CMV disease, then combined treatment should be attempted and can be expected to lead to a response in 90 percent of patients.[9]

Future Directions

One avenue of current research involves the use of oral preparations of both ganciclovir and foscarnet for the treatment of CMV disease. Treatment of this disease with oral agents will permit home therapy, and decrease the dangers of infection due to permanent in-dwelling catheters. The benefit of oral therapy on quality of life could be enormous. Both agents appear to have problems with absorption via the oral route, but trials of oral ganciclovir have shown some promising results. Less than ten percent of the dose of oral ganciclovir is absorbed into the bloodstream, and it appears that increasing the dosage has little effect on blood levels.[10] Nevertheless, early data suggests that use of high- dose oral ganciclovir may result in treatment success almost equal to the intravenous form and appears to be better tolerated. Although induction with oral ganciclovir may not be adequate, maintenance therapy with this drug has potential value.

Early studies of oral foscarnet have been more disappointing. Foscarnet is poorly absorbed from the gastrointestinal tract, resulting in diarrhea and serum levels too low to inhibit CMV.

Newer agents, such as a precursor of the anti-herpes drug, acyclovir, called valacyclovir, are also being studied for treatment and prophylaxis. Valacyclovir is better absorbed than ganciclovir, and is completely metabolized to acyclovir, resulting in serum concentrations similar to that achieved by intravenous administration of acyclovir. Another drug called HPMPC is also being studied, but appears to be too toxic for routine use. It is associated with severe damage to the kidney, although concurrent use of probenicid may help prevent this.

Conclusion

CMV has been implicated in disease throughout the gastrointestinal tract, where it results in significant illness and death. As patients with AIDS live longer due to advancements in diagnosis and treatment, we can expect the incidence of CMV infection to increase and disease due to this organism to take on even greater clinical significance. New treatments are needed, and a considerable amount of research is being conducted to erase this killer of AIDS patients.

1 Mintz L, et al. Annals of Internal Medicine, 1983; 99(3):326-9.

2 Guarda LA, et al. American Journal of Clinical Pathology, 1984; 81(5):549-57.

3 Dieterich DT, et al. Journal of Acquired Immune Deficiency Syndromes, 1991; 4 Suppl. 1:S29-35.

4 Wilson SE, et al. Annals of Surgery, 1989; 210(4):428-34.

5 Connolly GM, et al. Gut, 1989; 30(8):1033-9.

6 Dieterich DT, et al. American Journal of Gastroenterology, 1993; 88(4):542-48.

7 Ocular Complications of AIDS Research Group. New England Journal of Medicine, 1992; 326(4):213-20.

8 Dieterich DT, et al. IX International Conference on AIDS, June 1993, abstract PO-BO8-1263.

9 Dieterich DT, et al. Journal of Infectious Diseases, 1993; 167(5):1184-8.

10 Jacobson MA, et al. Antimicrobial Agents and Chemotherapy, 1987; 31(8):l251-4.

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