TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies, Vol 5, No. 2, - Feb 25, 1991
Gabriel Torres, M. D.

ddC: Current Knowledge

Dideoxycytidine (ddC) has proven to be a potent inhibitor of HIV both in the test tube and in humans. In Phase I/II studies, conducted by the AIDS Clinical Trials Group (ACTG) to determine dosage and efficacy, ddC was administered to over 300 patients with AIDS or ARC. The trials showed that ddC effectively reduced viral reproduction as measured by p24 antigen levels (l). ddC also proved temporarily to increase T4 cell counts during the first eight to twelve weeks of therapy with gradual declines back to original T4 levels (2). The most frequent toxicity of ddC has been peripheral neuropathy, or nerve damage, primarily in the feet, which seems to occur more frequently at higher doses of drug (greater than 0.03 mg/kg). Symptoms of neuropathy include a sensation of pins and needles, numbness, and pain in the lower legs and feet. Symptoms seem to worsen temporarily after the drug is stopped (a phenomenon referred to as "coasting effect"). In severe cases, neuropathy has taken as long as six months to resolve (3). At lower doses of ddC (greater than 0.01 mg/kg) the neuropathy symptoms are less frequent and more readily reversible. Early identification of the symptoms and discontinuation of drug is the best way to prevent the neuropathy from progressing. Other less common side effects of ddC include skin rashes, mouth ulcers, elevated liver enzymes, and low platelet counts. Rare side effects, which have occurred in isolated cases include hearing loss, kidney failure, and abdominal pain.

ddC Availability

Under an "expanded access" program initiated in late September 1990, ddC became available for persons with AIDS and advanced ARC, who are unable to stay on AZT. Patients allowed to enter the program cannot tolerate AZT, show signs of progressive disease while on AZT, or are taking drugs incompatible with AZT.

To be classified as an "AZT-failure," a patient must have one of the following conditions after taking at least 500 mg/day of AZT for more than six months: three opportunistic infections (OIs) or cancers within six months of treatment; a decline in T4 cell counts by 50, compared to counts when AZT was initiated, or a T4 cell count of SO or less on two occasions one month apart; involuntary weight loss of 2-2.5 lbs. per week for at least four weeks; a measurable increase of virus as reflected in p24 antigen levels; or neurological deterioration or disability requiring special care and hospitalization.

To be classified as "AZT-intolerant," a person must have had one of the following reactions to AZT: anemia (decrease in hemoglobin of 2 gm/month); a depletion of white blood cells (total neutrophil count under 750); nausea or vomiting; severe headaches; psychosis; severe agitation or declining muscle strength (i.e., inability to climb stairs) from muscle damage (myopathy) caused by AZT.

"AZT ineligible" patients include those who require drugs that are incompatible with AZT, for example ganciclovir therapy for cytomegalovirus (CMV). Also considered "AZT ineligible" are patients who have never taken AZT, but have low white blood cell counts or severe anemia.

Additionally, patients who are ineligible for, or intolerant to ddI qualify for the ddC expanded access program. Although these patients are not required to demonstrate ddI intolerance, many who have had side effects from ddI may be candidates for ddC. These patients include those who have developed pancreatitis, hepatitis, elevated uric acid levels or severe diarrhea from ddI.

Hoffman-La Roche reports that more than 1,100 patients have been enrolled in expanded access programs for ddC. Of that number, only four patients have developed pancreatitis or elevated pancreatic enzymes, referred to as the amylase level. Of those four patients, two had a previous history of ddI-related pancreatitis.

If abdominal pain, nausea or vomiting develop for a patient on ddC therapy, the drug should be discontinued immediately and a medical evaluation for pancreatitis should be performed. If amylase levels are five times higher than normal, ddC should be discontinued even if the patient has no symptoms of pancreatitis. In two patients on ddC, according to Hoffman-La Roche, diabetes and elevated blood sugar levels were reported, possibly suggesting that ddC affects the pancreas.

For patients with less advanced disease, and T4 cell counts under 300 (or under 200 in asymptomatic patients) ddC is only available through clinical trials.

ddC or ddI

Most of the patients receiving ddC or ddI under expanded access programs are patients with advanced disease who have had more than one year of AZT therapy and who have most likely developed AZT resistance. Most of these patients have low T4 cell counts. Expanded access programs for ddI are detailed in Treatment Issues, vol. 4, no. 7.

The choice between ddC and ddI requires a careful assessment of the potential toxicities of each drug according to individual patient characteristics. Both drugs are tolerated well, yet require frequent monitoring (physical and neurologic examinations and laboratory assessments) in order to avoid adverse effects. The long-term effects of both drugs are still relatively unknown. Muscle wasting similar to the kind associated with long-term AZT use, has also been reported in several patients using ddI or ddC.

Patients who are at risk for pancreatitis due to predisposed conditions are probably better off choosing ddC over ddI. Some of the predisposing conditions include: previous history of alcohol abuse; pancreatitis in the past; elevated triglycerides, uric acid levels, or intravenous pentamidine. All of the above conditions may increase the risk of pancreatitis.

For those intolerant of or failing AZT and ineligible for expanded access, the Community Program for Clinical Research on AIDS (CPCRA), a federally-funded program conducting clinical trials at 18 community sites throughout the U. S., is sponsoring a trial comparing ddI versus ddC in patients with T4 cell counts less than 300. In New York, the trial is being conducted by the Harlem AIDS Treatment Group (contact Michelle Harding at 212-694- 4344). In Newark, New Jersey, the Community Research Initiative will conduct the trial (contact William Orr at 201-648-0350).

ddC and AZT

Ongoing clinical trials combining ddC and AZT are investigating whether this combination offers an advantage over therapy with a single drug. Some trials compare ddC to AZT, others compare combinations of ddC and AZT, and still others evaluate the usefulness of switching back and forth between ddC and AZT 'every week or month.

In San Francisco, at the Sixth International Conference on AIDS, preliminary results of a complex trial comparing many different regimens were reported. The arms of this trial consisted of: low dose AZT (150 or 300 mg) combined with ddC (0.005 mg/kg); high dose AZT (600 mg) combined with ddC (0.01 mg/kg); or very low dose AZT alone (150 mg/day) (4,5). In June 1990, 43 of 55 patients Conclusion enrolled in this trial, were still on therapy. Two patients had to discontinue therapy because of neuropathy. Three patients had neuropathy that resolved and four developed low blood counts. All patients showed an early rise in T4 cell counts, which peaked between four and 12 weeks, followed by a gradual fall to original counts.

In November 1990, Dr. Douglas Richman gave an update of this trial at a meeting in Washington (6). So far, patients in each arm of the trial showed weight gain and rises in T4 cell counts. The high doses of ddC and AZT seemed to be more effective in suppressing viral reproduction, as measured by p24 antigen levels than the low-dose combinations of ddC and AZT. The least effective regimen seemed to be AZT at 150 mg/day alone.

Combination AZT and ddC may have the dual benefits of preventing resistance and minimizing the toxicity of each drug. For example, if AZT and ddC are alternated every other week or month, the time off AZT will allow for bone marrow recovery and the time off ddC will allow for nerve tissue recovery. Additionally, none of the actual antiretroviral benefits of the drugs will be lost. One trial has shown that neuropathy was more common in patients with pre-existing neurologic abnormalities, patients on high-dose ddC, patients on weekly (as opposed to monthly) alternating and intermittent schedules (7).

In the test tube, HIV strains from patients on alternating ddC/AZT remain sensitive to AZT, whereas strains from patients on AZT alone are uniformly resistant to AZT (8). Intermittent schedules where patients are taken off both drugs for any length of time run the risk of resurgent HIV replication and disease progression while not taking drug.

Conclusion

Though neither alternating, intermittent or combination regimens of AZT and ddC are recommended for general usage, it is imperative that the final results of these clinical trials be made available as soon as possible, since approval of ddC is expected in the near future. Community physicians and their patients need to be educated on the most appropriate dosages, schedules and combinations in order to maximize the benefits and minimize the toxicities of AZT, ddC and ddI. A consensus conference to examine all existing data on ddC, including the data emerging from the expanded access protocol, must occur in the near future to formulate a recommendation on regimens to be used once ddC is approved.

References:

1 Yarchoan R et al. Phase I studies of ddC in HIV infection as a single agent and alternating with sidovudine. Lancet i:76- 81, 1988.

2 Merigan TC et al. Circulating p24 antigen levels and responses to ddC in HIV infections. Ann Intern Ned. 110: 189-194,1989.

3 Dubinsky RM et al. Follow-up of neuropathy from ddC. Lancet i: 832,1988.

4 Powderly W et al. Toxicity associated with ddC. Lancet i: 1106,1990.

5 VIth Int Conf on AIDS, abstracts ThB. 23, SB. 426, San Francisco, June, 1990.

6 AIDS Clinical Trial Group Meeting, Nov. 11-14, 1990, Washington, D. C.

7 VIth Int Conf on AIDS, abstract SB. 425, San Francisco, June, 1990.

8 VIth Int Conf on AIDS, abstract ThA. 263, San Francisco, June, 1990.

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