Much needed research to determine the best prophylactic regimen for Pneumocystis carinii pneumonia has been on going in the form of clinical trials. In the past few months, two important conferences, the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Disease Society of America (IDSA) Annual Meeting, both had numerous presentations on the outcomes of these studies.
Daily TMP/SMX Preferred for PCP Prophylaxis
The two-drug combo trimethoprim/sulfamethoxazole (TMP/SMX, marketed under the brand names Bactrim or Septra) is the most effective antibiotic for prevention of PCP, especially among those who have already experienced a bout of pneumonia; yet the best regimen and dosage schedule has remained a dilemma until now. The most commonly used regimens have been either daily or thrice-weekly doses of double-strength TMP/SMX (160 mg/800 mg). Other doses utilized by some clinicians include daily regimens of single-strength TMP/SMX (80 mg/400 mg), three consecutive doses of double-strength TMP/SMX per week or an every other day regimen. Previous studies have shown that TMP/SMX is more effective than aerosolized pentamidine (AP) and oral dapsone, and that the single- and double-strength regimens are equivalent in effect.
The Community Programs for Clinical Research on AIDS (CPCRA) recently released the results of the largest clinical trial ever conducted for PCP prevention, comparing the safety and efficacy of daily versus thrice-weekly double strength TMP/SMX in HIV-infected patients at high risk for PCP (presented at ICAAC as poster I-146). The goal of the study was to evaluate which dose was more effective in preventing both PCP and toxoplasmic encephalitis, as well as which was less toxic. Between August 1992 and August 1995, the trial enrolled 2,625 patients who were followed for an average of 34 months. Participants had a CD4 count of 200 or less at entry and no prior PCP (this group used TMP/SMX for primary prevention) or had a prior episode of PCP (this group used TMP/SMX for secondary prevention). The primary endpoint was the development of confirmed or probable PCP.
The patient population was mostly minority (45% black and 15% Latino). Sixteen percent were female and a third had a history of injecting drug use. Most of the patients (2,212) were on primary prophylaxis while 413 were on secondary prophylaxis. The mean CD4 count at entry was lower for the thrice-weekly group (128) than for the daily group (136). Twenty-one percent of the patients were positive for toxoplasma antibodies, reflecting a previous infection with the encephalitis-causing microbe. This group was also followed for the development of encephalitis.
Among all study participants the rates of PCP were similar for the two treatment groups (3.5% versus 4.1% per 100 person-years) and the rates of PCP did not differ in either the primary or secondary prophylaxis groups. Survival rates were also similar between the two groups. However, patients given daily TMP/SMX as secondary prophylaxis had a significantly prolonged survival compared to those taking thrice-weekly TMP/SMX (death rate of 32.5% versus 35.7% per 100 person-years). Also, the rates of bacterial pneumonia were significantly lower among those on daily TMP/SMX as compared to those on thrice-weekly TMP/SMX (7.5% versus 8.6% per 100 person-years). The rates of toxoplasmosis encephalitis were similar among the two groups (1.9% versus 2.0%), though due to the low number of cases of encephalitis the study could not reliably determine the relative benefit of the two doses of TMP/SMX on this endpoint. (A report from Barcelona presented at ICAAC comparing high dose TMP/SMX, more than three times a week or less, did show a significant protective effect of the high dose for primary prophylaxis of toxoplasmosis [ICAAC poster I-140].)
In an analysis of the combined endpoint of PCP and bacterial pneumonia, daily TMP/SMX was also significantly more effective than thrice-weekly TMP/SMX. The overall rates of side effects were similar between the two groups. The most common adverse effects were rash, fever and low blood cell counts. The rate of permanent drug discontinuation was higher among those on daily TMP/SMX than those on thrice-weekly (168 versus 126), but this difference was only seen in the primary prophylaxis group. Wafaa El-Sadr, M.D., the principal investigator for the study, concluded that the overall results indicate that patients eligible for PCP prophylaxis should be advised to take double-strength TMP/SMX on a daily basis. She does not think that daily single-strength dosing is advisable since it is essentially equivalent to a thrice-weekly double-strength regimen.
At ICAAC in Toronto this month, James Stanford, M.D., presented data on an American Foundation for AIDS Research (AmFAR) trial (LB-10) that addressed an important point: Although TMP/SMX is a highly effective PCP prophylaxis, many people have been forced to discontinue treatment due to side effects. The AmFAR study evaluated the best method for overcoming such common adverse reactions as fever and rash. Because of the superior efficacy, low cost and relative safety of TMP/SMX, it is preferable, if possible, to desensitize a patient to side effects rather than use other agents. In the study, persons with a history of drug-associated non-life-threatening rash or fever resulting in the discontinuation of TMP/SMX were randomized into two groups. One group received a six-day regimen of incremental dose escalation to single-strength TMP/SMX (see chart for dosing schedule). The other group was given a direct rechallenge with one single-strength TMP/SMX tablet. Antihistamines were given to both groups one day prior to the first dose and throughout the reintroduction period. The primary outcome was the proportion of patients able to take one single-strength TMP/SMX for six months. (This study does not address the issue of escalating the dose to a double-strength tablet daily. Double-strength is the preferred dose according to the Public Health Service Guidelines on Opportunistic Infections. Many doctors, nonetheless, use single-strength and the guidelines note that one single-strength tablet per day is also highly effective.)
The six-day dose escalation method proved to be significantly more successful (80% of participants able to complete six months of treatment) than the direct rechallenge method (55% completion rate). Baseline demographics were similar in both groups. Dr. Stanford pointed out that even with the inferior method of direct rechallenge, 55% of patients were successful, and stated that this may be a reasonable approach for those who cannot tolerate dose escalation.
Atovaquone vs. Dapsone or Aerosolized Pentamidine
For patients who remain intolerant of TMP/SMX, another CPCRA study presented by Dr. El-Sadr as a late-breaker at IDSA provided information on alternative methods for PCP prophylaxis (abstract 769). This study compared dapsone at 100 mg daily to the new liquid formulation of atovaquone (Mepron) at 1500 mg daily. (The new version of atovaquone is much better absorbed by the gut than the older tablets.) The trial followed 1,057 patients with a median CD4 count of 60 and a history of TMP/SMX intolerance. Just over 50% of patients were on dapsone at entry. The two regimens had similar efficacy as PCP prophylaxis (16.8% incidence of PCP on atovaquone versus 20.7% on dapsone). Survival and termination due to adverse events were also similar, but atovaquone was generally better tolerated. The study suggests that for TMP/SMX intolerant patients, atovaquone may be a better choice for first-line prophylaxis treatment, but those who are currently tolerating dapsone may remain on it.
There was also a poster at IDSA on atovaquone for prophylaxis in 476 TMP/SMX-intolerant patients (poster 518). Results from Glaxo Wellcome trial 213 comparing atovaquone suspension with aerosolized pentamidine (AP) were reported. Patients with a history of PCP or a CD4 cell count below 200 were randomized to receive either low dose atovaquone at 750 mg once daily, high dose atovaquone at 1500 mg once daily or AP at 300 mg monthly. There was no statistical difference in survival or incidence of PCP among the groups (22% of patients in the low dose group, 20% in the high dose group and 17% in the AP arm experienced an episode of PCP during the study). Median duration of follow-up was one year. Rash occurred more frequently in the atovaquone arms and bronchospasm occurred more frequently in the AP arm. The study investigators concluded that atovaquone, at either low or high dose, and AP have similar safety and efficacy for PCP prophylaxis.
One caveat is that atovaquone is not FDA-approved for use as PCP prophylaxis. (Glaxo Wellcome, however, is planning to submit a New Drug Application for this purpose in December or January at the 1500 mg liquid dose, based on the two above-mentioned studies.) In fact, TMP/SMX is currently the only widely used medication indicated for both prophylaxis and treatment of PCP. At this point, atovaquone is approved only for treatment of mild-to-moderate PCP in TMP/SMX-intolerant patients; AP is indicated for prophylaxis but not treatment (a 600 mg formulation of AP has been approved for treatment, however, this product is not commercially available); and dapsone is indicated for leprosy. Despite not having a specific FDA indication, these drugs may be prescribed off-label. (This means they can be used for a condition other than the one for which they were approved.)
Physicians frequently use off-label drugs to treat persons with HIV and AIDS, as well as for other diseases. Pharmaceutical companies will probably begin marketing drugs more aggressively for off-label purposes due to recent FDA reforms (see second to last article in this issue). The main drawback for patients is that there can be problems obtaining insurance reimbursement when a drug is prescribed off-label.
TMP/SMX Desensitization Protocol
| ||% of Single-Strength Dose||Volume* Frequency||Amount of TMP/SMX|
|Day 1||12.5%||1.25 ml once||10 mg/50 mg|
|Day 2||25%||1.25 ml twice||20 mg/100 mg|
|Day 3||37.5%||1.25 ml thrice||30 mg/150 mg|
|Day 4||50%||2.5 ml twice||40 mg/200 mg|
|Day 5||75%||2.5 ml thrice||60 mg/300 mg|
|Day 6||100%||1 tablet once||80 mg/400 mg|
*This protocol uses a standard strength TMP/SMX suspension (TMP 40 mg/SMX 200 mg per 5 ml) that can be prepared by a pharmacist.