Anti-HIV and tuberculosis (TB) drugs work well and safely together according to a number of studies presented to the Tenth Conference and Retroviruses and Opportunistic Infections in Boston today. TB is the most common AIDS defining opportunistic infection and can occur in people with relatively intact immune systems.
Five studies conducted in a range of resource settings found that when HAART and anti-TB therapy were administered at the same time, patients experienced an improvement in CD4 counts, reduction in viral load, and TB cure. Although co-treatment with HAART and TB therapy was found to be safe, one study found that a lower dose of the anti-TB drug rifabutin did not reach therapeutic levels when HIV was treated with efavirenz-based regimens.
US investigators found that in a trial involving 169 HIV/TB coinfected patients, with low CD4 counts (average 90 cells/mm3) and high viral loads (average 5.3 log), HAART was successful at improving immune function and decreasing HIV replication when administered at the same time as anti-TB therapy consisting of rifabutin and isoniazid (with pyrazinamide and ethambutol for the first two months). Average CD4 count increased by 61 cells and viral load fell by an average of 1.6 log. TB therapy had a cure rate of 95%. When the investigators compared their findings with a pre-HAART study into TB treatment in HIV patients (CPCRA 019/ACTG 222), they found that although baseline CD4 counts were similar in both studies, survival was significantly better in TB treated patients post-HAART (85% versus 95%) after twelve months of TB treatment. They conclude “despite the complexities of antiretroviral therapy during TB treatment…AIDS p[atients] can be successfully treated with HAART while receiving rifabutin-based TB therapy. Use of HAART was associated with improved survival after TB diagnosis.”
A study conducted in the HIV care clinic in Ahmedabad, India compared CD4 counts in two groups of HIV patients. Ninety-nine patients (Group A) were also coinfected with TB and received anti-TB therapy based on rifampicin, and 98 (Group B) were just HIV-infected. Anti-HIV therapy consisted of efavirenz and either AZT and 3TC or d4T and 3TC. At baseline, CD4 counts were lower in TB patients (104 cells/mm3) than group b patients (130 cells/mm3), however after six months of HAART and anti-TB treatment CD4 counts were comparable for both arms of the trial at 276 cells/mm3 (Group A) and 278 cells/mm3 (Group B). By month nine of the study, CD4 counts were higher in the patients receiving TB therapy (306 cells/mm3) than Group B patients (270 cells/mm3. On the basis of these finding the investigators conclude, “co-administration of rifampicin and efavirenz is well tolerated and doesn’t affect antiretroviral potency as measured by the rise in CD4 counts. In India and other countries where TB is a common opportunistic infection, efavirenz therapy can be offered along rifampicin-based anti-TB treatment.”
Resistance to anti-TB drugs in the rifamycin (rifampin and rifabutin) class was found to be associated with low CD4 counts in a study conducted amongst 109 HIV-positive patients in Baltimore between 1993 and 2001. In a retrospective investigation, cultures were obtained from all patients with rifamycin-susceptible TB who completed a course of directly observed anti-TB therapy. TB treatment was daily for three weeks and then twice weekly. Data on TB recurrence was gathered and DNA fingerprinting undertaken to identify drug-resistant TB strains. TB recurred in nine patients. Their average CD4 count of 50 cells/mm3, at which level they would be vulnerable to life threatening opportunistic infections. Sputum samples found that resistance to the rifamycin class of anti-TB drugs was present in three patients, all of whom had received rifampin. None were identified in patients treated with rifabutin. The investigators conclude, “among HIV patients, low CD4 count was the only risk factor for TB relapse” adding that rifamycin resistance “was only seen in patients with low CD4 counts.”
The safety and efficacy of efavirenz-based HAART regimens in TB patients was demonstrated by a Brazilian study presented to the conference. Forty-four patients were enrolled to the study. TB therapy consisted of rifampicin, and isoniazid for nine months with pyrazinamide for the first two months. HAART consisted of two nucleoside analogues plus efavirenz at 600mg daily. The study lasted three years, and at baseline patients had an average CD4 count of 106 cells/mm3, a 6 log viral load and weighed 51 kg. After two years, average CD4 count had increased to 341 cells/mm3, viral load had fallen to 1.4 log and weight increased by 21 kg. Three patients died in the first month of therapy, two due to an infection and one with treatment-related renal failure. Over 80% had resolution of TB and responded to HAART, of the nine treatment failures, six abandoned their therapy within six months. The investigators therefore conclude “efavirenz 600mg daily dose is sufficient to treat HIV/TB patients with [a] rifampin containing regimen.”
However, a study conducted in Florida involving 20 patients, found that use of efavirenz with rifabutin can affect the bioavailability of the anti-TB drug. Pharmacokinetic drug levels were tested in all HIV-positive TB patients treated with rifabutin and efavirenz containing regimens in an HIV clinic in Florida between June 2000 and September 2002. The dose of rifabutin was 300mg or 450mg twice weekly, with the efavirenz dose 600mg daily. Before HAART was initiated tests to evaluate CD4 count, viral load and blood levels of rifabutin and isoniazid (two and six hours after dosing) were performed. Follow-up tests included standard CD4 and viral load tests as well as further tests to look at blood levels of the anti-TB drugs two and six hours after taking them, and peak and trough levels of efavirenz (four and 24 hours). These tests were performed two to six weeks after starting anti-HIV therapy. There was significant improvement in CD4 count and a reduction in viral load. Six patients were treated with a 300mg dose of rifabutin and 16 the 450mg dose. Blood levels of rifabutin were 0.17 and 0.50 at two and six hours pre-HAART on the 450mg dose and 0.16 and 0.21 at the same intervals two weeks after starting HAART. For the 300mg dose two and six hour levels were 0.12 and 0.15 pre-HAART and 0.14 and 0.11 two weeks after starting anti-HIV therapy. Efavirenz levels at four and 24 hours were within expected ranges. The investigators conclude, “in patients on concurrent rifabutin and efavirenz, neither rifabutin or efavirenz levels were significantly affected except for lower six hour rifabutin levels after efavirenz initiation. Patients on rifabutin 300mg did not appear to reach the expected PK range, supporting the current recommendation for rifabutin of 450mg twice weekly when using an efavirenz-containing” regimen.
Further information on this website
Tuberculosis - Overview
Burman W et al. Use of antiretroviral therapy during treatment of active tuberculosis with a rifabutin-based regimen. Tenth Conference and Retroviruses and Opportunistic Infections, Boston, abstract 136, 2003.
Patel A et al. To study the safety and antiviral efficacy of concomitant use of rifampicin and efavirenz in antiretroviral-naïve tuberculosis coinfected HIV-1 patients in India. Tenth Conference and Retroviruses and Opportunistic Infections, Boston, abstract 138, 2003.
Nettles R et al. Tuberculosis relapse and acquired rifamycin resistance in HIV-1 infected persons is associated with low CD4 count, but is not more common with rifabutin than rifampin. Tenth Conference and Retroviruses and Opportunistic Infections, Boston, abstract 137, 2003.
Redral-Samapio D et al. Efficacy of efavirenz 600mg dose in ARV therapy regimen for HIV patients receiving rifampicin in the treatment of tuberculosis. Tenth Conference and Retroviruses and Opportunistic Infections, Boston, abstract 784, 2003.
Hollender E et al. The concomitant use of rifabutin and efavirenz in HIV/TB co-infected patients. Tenth Conference and Retroviruses and Opportunistic Infections, Boston, abstract 785, 2003.