IAS: Low Dose of Nevirapine OK for HIV/TB

SYDNEY, July 24 -- In patients who have both HIV and tuberculosis, doctors can use a relatively low dose of nevirapine (Viramune) in combination with rifampin (Rifadin), researchers said here.
In a randomized clinical trial in Thailand, nevirapine at 400 milligrams a day worked as well as 600 milligrams in controlling HIV, according to Anchalee Avihingsanon, M.D., of the Thai Red Cross AIDS Research Center in Bangkok.
Despite rifampin's known interaction with nevirapine -- reducing serum levels by 20% to 50% -- the higher dose isn't needed, Dr. Avihingsanon told attendees at the International AIDS Society meeting.
In fact, she said, the study's data monitoring committee halted the trial early, arguing that the results were so clear there was no need to continue investigating the question.
The usual choice for people with both HIV and TB is a regimen based on efavirenz (Sustiva), she said. But doctors often turn to nevirapine when efavirenz is ruled out -- by allergy, pregnancy, or the simple unavailability of the drug.
But it has not been clear whether the nevirapine dose needs to be increased to counter the drug interaction with rifampin, Dr. Avihingsanon said.
To try to settle the question, she and her colleagues enrolled 32 patients who had both active TB and HIV and whose CD4 cell counts were less than 200 cells per microliter.
They were randomized to get either a low dose of 400 milligrams of nevirapine a day (in two doses) or a high dose of 600 milligrams administered once a day.
The researchers planned to treat the patients for 48 weeks, but the study was halted when a 24-week interim analysis showed essentially no difference in control of the HIV, she said.
At 24 weeks:
On an intention-to-treat basis, the proportion of patients with HIV RNA less than 50 copies per milliliter was 62% in the high-dose arm and 50% in the low-dose arm, which was not significantly different.
The median increase in CD4 cell count was 106 in the high-dose arm and 44 in the low-dose arm, which again was not significantly different.
On the other hand, she said, 25% of patients in the high-dose arm displayed nevirapine hypersensitivity and had to stop taking the drug, compared with only 6% in the low-dose arm.
There may be a lower limit to low-dose nevirapine, though. The study design included a two-week lead-in period, in which patients in the low-dose arm were given 200 milligrams a day of nevirapine and those in the high-dose arm received 400 milligrams, given in two doses.
During that period, Dr. Avihingsanon said, suboptimal nevirapine levels were seen in patients in the low-dose arm, suggesting that a 200-milligram dose should not be used.
The "encouraging" finding implies that lower doses of nevirapine don't predict poor clinical outcomes in this situation, said Gerald Friedland, M.D., of Yale University, who chaired the session.
"Lower doses are probably okay and higher doses are associated with more side effects and toxicity," Dr. Friedland said.
Whether the finding can be generalized to other populations -- especially physically larger Caucasians -- remains unclear, he said.

IAS: TB and HIV Therapy Can Co-Exist

SYDNEY, July 23 -- Tuberculosis and HIV therapy can take place at the same time without the risk of long-term HIV treatment failure, researchers said here.
In a prospective longitudinal cohort study of HIV patients with and without TB, the long-term risk of HIV treatment failure was the same regardless of TB therapy, according to Ketan Patel, M.D., of the Infectious Diseases Clinic in Ahmedabad, India.
The finding appears to put to rest fears that TB treatment with rifampin (Rifadin) increases the risk of simultaneous treatment with efavirenz (Sustiva); Dr. Patel told an oral abstract session of the International AIDS Society meeting. Rifampin is known to reduce plasma levels of many HIV drugs, including efavirenz.
Dr. Patel and colleagues showed in 2004 that co-administration of rifampin and an HIV regimen based on efavirenz at 600 mg/day had no effect on the anti-viral efficacy of the HIV drugs.
But it remained possible, he said, that the durability of the response might be affected by the interaction of the drugs. To find out, he and colleagues followed 383 patients for a minimum of 12 months and up to three years.
Of those, 195 had both TB and HIV and were treated for nine months with a rifampin-based TB regimen, while at the same time getting efavirenz and other HIV medications.
At the beginning of therapy, the TB group had an average CD4 cell count that was significantly lower (P=0.0005) than those without TB -- 90 versus 126 cells per microliter of plasma.
But by the end of the TB treatment, there was no significant difference in CD4 cell count between the groups, Dr. Patel said. Indeed, he added, CD4 cell improvements were comparable between the groups et every point up to three years of follow-up.
The key indicator was immunological treatment failure, he said, which was defined as a drop of more than 30% in the CD4 cell count from the start of therapy.
The study found that 23 of the TB group and 19 of the non-TB patients had an immunological failure -- or 11.8% versus 10.1% -- which was not significantly different.
Even when patients lost to follow-up were counted as failures, he said, the treatment failure rates did not differ significantly between the arms.
Adverse events were also similar between the groups, Dr. Patel said, with the exception that there was more hepatitis in the TB group -- 26 cases versus four (P=0.0001).
The take-home message of the study is that "treatment of HIV and TB co-infection is possible to do with concomitant therapy with both good short- and long-term outcomes," commented Gerald Friedland, M.D., of Yale, who chaired the session.
Dr. Friedland said more studies are needed to pinpoint "the perfect time" to start treating both infections, but this research suggests that co-therapy fears are exaggerated.
It appears that "concerns about the dangers of anti-retrovirals are being outweighed by the mortality that might be prevented," he said, "but we need more studies to show that."

Standard 6-Month TB Therapy May Be Insufficient to Prevent Relapse in Patients With HIV

May 31, 2007 — Standard 6-month therapy for tuberculosis (TB) might be insufficient to prevent relapse in patients with HIV, according to the results of a study reported in the June 1 issue of the American Journal of Respiratory and Critical Care Medicine.
"The preferred regimen for the treatment of drug-susceptible tuberculosis in HIV-uninfected individuals is a 6-month, rifamycin-based regimen that includes pyrazinamide during the initial 2-month phase," write Payam Nahid, from the San Francisco General Hospital, University of California in San Francisco, and colleagues. "There continues to be controversy about the optimal duration of treatment for tuberculosis in HIV-infected patients."
The objective of this study was to evaluate treatment outcomes in a low-incidence setting, where HIV-infected patients were managed at a TB control program without significant resource limitations and were stratified by duration of rifamycin-based TB therapy.
The investigators retrospectively reviewed data on all 700 patients with TB reported to the San Francisco Tuberculosis Control Program from 1990 to 2001 with follow-up for up to 12 months after treatment completion.
Of the 700 patients, 264 (38%) were HIV-infected, 315 (45%) were not infected, and 121 (17%) were not tested. For the HIV-infected patients, the mean duration of treatment was extended to 10.2 months, compared with 8.4 months for uninfected patients and those of unknown HIV status (P < .001). Rifamycin-based therapy for 6 months was given to 17% of the HIV-infected patients and to 37% of the other patients.
The relapse rate was 9.3 per 100 person-years in HIV-infected patients, compared with 1.0 in HIV-uninfected/unknown patients (P < .001). HIV-infected patients who received a standard 6-month rifamycin-based regimen were more likely to relapse than were those who were treated for longer periods (adjusted hazard ratio, 4.33; P = .02).
Compared with HIV-infected individuals who were treated daily, those who received intermittent therapy were also more likely to relapse (adjusted hazard ratio, 4.12; P = .04). Use of highly active antiretroviral therapy was associated with faster conversion of smears and cultures and with increased survival.
"HIV-infected patients who received a 6-month rifamycin-based course of tuberculosis treatment or who received intermittent therapy had a higher relapse rate than HIV-infected subjects who received longer therapy or daily therapy, respectively," the authors write. "Standard 6-month therapy may be insufficient to prevent relapse in patients with HIV."
Study limitations include potential biases, such as the effect of physician preference for prolonging treatment in HIV-infected patients; difficulty in determining cause of death; retrospective design; database initiated in the early 1990s when the immune reconstitution syndrome in HIV-infected patients was first described, allowing limited data acquisition on this syndrome; and differential attrition in the 2 groups.
"Despite the varying recurrence rates noted in the literature, the generally recommended treatment for HIV-infected patients with tuberculosis is 6 months of a rifamycin-based regimen. Based on our findings, we recommend...further research...to identify the most efficacious duration of therapy and the optimum timing for HAART [highly active antiretroviral therapy] in the treatment of HIV-related tuberculosis."
The National Institutes of Health (NIH) through the NIH Roadmap for Medical Research, National Institute of Allergy and Infectious Diseases, and the American Lung Association supported this study. None of the authors report any relevant financial relationships.
In an accompanying editorial, David C. Perlman, MD, from Beth Israel Medical Center in New York City, and colleagues noted that regimens should not be evaluated solely on the basis of failure-relapse rates, but perhaps should be evaluated on rates of acquired resistance.
"Erratic access to secondline anti-TB drugs in areas with high HIV prevalence has proven a fertile ground for the emergence of XDR-TB [extensively drug-resistant tuberculosis]," the editorialists write. "However, in the treatment of HIV-related TB, access to essential drugs alone is far from sufficient. To avert a looming disaster, there is an urgent need to strengthen both the HIV and TB control programs in areas with high rates of HIV-related TB."
None of the authors report any relevant financial relationships.
Am J Resp Crit Care Med. 2007;175:1102-1103, 1199-1206.