Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 9 - October 1994
Gabriel Torres, M.D.

Cytomegalovirus Infection

The long-awaited trial using oral ganciclovir to prevent CMV disease was not formally presented at the conference, although a summary of the data was presented by W. David Hardy, M.D., at a satellite symposium sponsored by the UCLA AIDS Institute on the day after the conference. The trial enlisted 750 HIV-positive patients with CD4 counts below 50 (or below 100 plus a history of AIDS-related illnesses). Subjects were randomized to receive 1,000 mg of oral ganciclovir or placebo every eight hours and followed with ophthalmologic exams every two months for the development of CMV retinitis. An interim analysis found that at ten months, only sixteen percent of the oral ganciclovir group had contracted CMV retinitis, compared to 30 percent of the placebo group. This was a highly statistically significant difference.

An on-going trial by the Community Program for Clinical Research on AIDS (CPCRA) that followed almost 1,000 patients with CD4 counts less than 100 has not observed a delay in the onset of symptomatic CMV with oral ganciclovir. Participants started with slightly higher CD4 counts on average than in the first study, though, and their observational period was three months shorter. Also, they did not have the ophthalmologic exams, so some asymptomatic CMV infections may have been missed. Participants in both trials now will be given the option of open-label oral ganciclovir therapy.

Several posters provided helpful data for managing active CMV infections:

- A 31-person Spanish study[1] evaluated ganciclovir (ten milligrams per kilogram of body weight) or foscarnet (100 mg/kg) given as thrice weekly infusions for maintenance therapy in patients with CMV retinitis. There were seventeen relapses (51 percent) and 22 deaths (66 percent) after a mean follow-up of seventeen weeks. These rates are similar to those seen with the standard daily or five times weekly maintenance therapy using either drug. Similarly, a German study[2] of gastrointestinal CMV found little difference in effectiveness whether induction therapy with foscarnet infusions were administered for five or for seven days per week over a period of three weeks. The option of skipping infusion days, especially on weekends when clinics are closed, will reduce the extent of hospitalizations required for CMV disease.

- Two posters[3,4] described the use of ganciclovir, foscarnet or a combination of both drugs for the treatment of CMV polyradiculopathy, a spinal cord and nerve root inflammation. CMV polyradiculopathy usually leads to paralysis and incontinence. At least half of the patients exhibited improvement in neurological function and clearing of CMV from blood and cerebrospinal fluid.

- Various studies also examined the usefulness of the CMV blood antigen test to monitor patients with CMV disease during antiviral therapy. One poster[5] described how bloodborne CMV antigen rose prior to the clinical deterioration and also correlated with the appearance of drug-resistant CMV. The authors concluded that the CMV antigen test may be an important tool for detecting both failing CMV therapy and the emergence of ganciclovir- or foscarnet-resistant viral strains.

Pneumocystis Carinii Pneumonia

Many PCP reports at the conference focused on the problem of patients' intolerance to available drugs. Some presentations looked at the use of desensitization techniques to overcome allergies to the sulfa component of Bactrim or Septra: These allergic reactions seem to be related to an inability to metabolize sulfa breakdown products due to a glutathione deficiency common in HIV-positive patients.

One regimen presented by the Conant Medical Group[6] showed an 84 percent success rate in a retrospective analysis of 100 sulfa-allergic patients given a standard desensitization regimen with trimethoprim/sulfamethoxazole (TMP/SMX, the generic name for Bactrim and Septra). Since only one successfully desensitized patient (1.2 percent) developed PCP and toxoplasmosis, the researchers concluded that desensitization should be offered to all sulfa-allergic patients. Unfortunately, no comparative prospective study comparing desensitization merely to deferred rechallenge with a single or double strength tablet of TMP/SMX has been reported to date.

A 214-person Italian study[7] compared monthly to twice monthly dosage of aerosolized pentamidine (AP) (300 mg) for preventing PCP after a first attack (secondary prophylaxis). After a median follow-up of 200 or 240 days, depending on the group, fourteen episodes of PCP occurred in the once monthly group, compared to five in the twice monthly group. The researchers concluded that twice monthly aerosolized pentamidine is superior to once monthly treatment and suggested that the drug be used in cases of sulfa intolerance.

Studies conducted by the U.S. AIDS Clinical Trials Group (ACTG trials 081 and 021) have demonstrated that aerosolized pentamidine is just as effective as dapsone for primary prophylaxis, yet significantly less effective than TMP/SMX for secondary prophylaxis. For those persons intolerant to both dapsone and TMP-SMX, twice monthly aerosol pentamidine seems a reasonable alternative.

Dr. Hardy at the UCLA symposium presented a summary of the data from ACTG 108, a three-week study comparing three oral treatment regimens for mild-to-moderate PCP: trimethoprim/sulfamethoxazole, dapsone/trimethoprim and clindamycin/primaquine. This study enrolled 247 patients with mild PCP and found no difference in efficacy or toxicity among the three regimens, a reassuring fact for those who treat PCP with alternative regimens in an outpatient setting.

Mycobacterium Avium Complex

Prevention of disseminated MAC infections in patients with advanced HIV disease was the subject of two major reports:

- The rifabutin treatment IND data were presented[8] describing the experience of 2,560 people on the open-label. The median duration of prophylaxis was 260 days. Abdominal pain, nausea and diarrhea were common side effects. Breakthrough MAC infections occurred most frequently in participants with CD4 counts below 50 (5.3 percent).

- Preliminary information from an Abbott Laboratories placebo-controlled trial of clarithromycin was described in an oral presentation.[9] To date, 682 patients have been enrolled in the U.S. and Europe, of which 308 have withdrawn, many to pursue prophylaxis with rifabutin after its approval. Fifty-seven breakthrough MAC infections occurred, of which 48 remained sensitive to clarithromycin and six were highly resistant. The predicted versus observed incidence rate of MAC indicated that disseminated MAC has been reduced by 40 percent, an effect presumed to be related to clarithromycin. The efficacy data will be unblinded in October, and this inference may be confirmed.

Tuberculosis

The magnitude of the TB problem worldwide remains staggering: The World Health Organization estimates a current total of 700,000 cases of active TB among the HIV-positive population and that another ten million HIV-positive individuals have latent TB infections.

Relapse rates for treated TB vary throughout the world from 6.5 percent in Europe and the United States to 16.7 percent in Kenya. Some of these relapses may be due to reinfections with new strains of TB. The rate of protection using isoniazid (INH) was demonstrated in a study from Zambia, which showed that the drug reduced the incidence of reactivated TB from 16.2 percent to 1.8 percent. Another study from Barcelona showed that within an eighteen month follow-up period INH reduced the risk of reactivation from 18.5 percent to 6.7 percent.10

An important TB prophylaxis study was presented as a poster by a group from Johns Hopkins University.11 Conducted in Haiti, the study compared the effectiveness of two regimens for the prevention of initial attacks of active tuberculosis in HIV-positive, PPD- (skin test-) positive adults. Seven hundred eighty-four participants were randomized to receive either twice weekly isoniazid (800 mg twice weekly) for six months or a combination of rifampin and pyrazinamide twice weekly for two months. During the first ten months of follow- up, the risk of tuberculosis was 0.8 percent in the INH group versus 3.5 percent in the rifampin/pyrazinamide group. After the first ten months, no significant differences were noted in the rates of TB, nor was there a survival difference. The authors concluded that the difference in rates of breakthrough TB appeared to be related to different durations of prophylaxis.

A similar CPCRA study is comparing a year of daily INH to two months of daily rifampin/pyrazinamide in the same population. However, enrollment in this study is proceeding quite slowly, and it appears that conclusive documentation of the best TB prevention regimen will take some time.

1 Mallolas J et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; II(abstract PB0587):143.

2 Salzberger B et al. Tenth international conferenceII(abstract PB0519):127.

3 Karmochkine M et al. Tenth international conference. II(abstract PB0520):127.

4 Espinoza LA et al. Tenth international conference. II(abstract PB0521):127.

5 Hansen KK et al. Tenth international conference. II(abstract PB0528):128.

6 King C et al. et al. Tenth international conference. II(abstract 388B):25.

7 Rizzardi GP et al. Tenth international conference. II(abstract PB0612):150.

8 Gordin F et al. Tenth international conference. II(abstract 557B):70.

9 Pierce M et al. Tenth international conference. II(abstract 558B):70.

10 Gatell JM. Tenth international conference. II(abstract PS26):48.

11 Neal CJ et al. Tenth international conference. II(abstract PB0681):166.

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