HIV-positive patients who receive the standard tuberculosis therapy consisting of six months treatment with a rifamycin-based regimen are significantly more likely to experience a relapse of their tuberculosis than HIV-negative individuals treated with the same regimen, according to a retrospective American study published in the June edition of the American Journal of Respiratory and Critical Care Medicine.
The study involved 700 individuals who received treatment for tuberculosis in San Francisco between 1990 and 2001. The investigators found that the only factors associated with relapse of tuberculosis amongst HIV-positive patients were shorter duration of tuberculosis treatment and being prescribed a regimen of anti-tuberculosis drugs involving intermittent dosing. HIV-positive individuals who received potent antiretroviral therapy during their tuberculosis treatment were significantly less likely to relapse, had a quicker response to tuberculosis therapy, and experienced fewer side-effects related to their tuberculosis treatment.
Standard treatment for drug-sensitive tuberculosis consists of six months of therapy with a rifampicin-based regimen. For the first two months, a combination of four anti-tuberculosis drugs is typically prescribed, with treatment continuing for a further four months with two drugs.
Clinical trials suggest that this six-month regimen of therapy is equally effective in HIV-positive and HIV-negative individuals, and as a result treatment guidelines endorse this regimen in all individuals with drug-sensitive tuberculosis, regardless of their HIV infection status.
Investigators in San Francisco wished to determine the outcome of this treatment regimen in HIV-positive and HIV-negative patients with culture-positive tuberculosis. They therefore performed a retrospective analysis involving 700 patients treated for tuberculosis in the city between 1990 and 2001. A total of 264 (38%) of these individuals were HIV-positive, 315 (45%) were HIV-negative and 121 (17%) were of unknown HIV status. A review of the medical records of the patients of unknown HIV status convinced the investigators that these individuals were of low risk of HIV and they were therefore included with the HIV-uninfected patients in the investigators’ analyses.
Patients were considered cured if they completed their treatment; their cultures converted to negative; and, their symptoms resolved. Recurrence was defined as a second episode or tuberculosis after treatment was completed. Cultures were genotyped to determine if patients were experiencing a relapse of their initial episode of the infection or had been reinfected. Genotyping showed that all the patients in the study who had a recurrence of tuberculosis were experiencing a relapse of their initial infection.
Directly observed therapy was provided to the majority of patients, and those receiving once-, twice-, or thrice-weekly therapy were defined as receiving intermittent therapy, whilst those who were provided with anti-tuberculosis drugs five or seven days a week were categorised as receiving daily treatment.
For HIV-positive patients, information was also gathered on the use of potent antiretroviral therapy. Rifabutin was prescribed instead of rifampicin in patients taking anti-HIV treatment.
The investigators noted that HIV-positive patients were significantly more likely than HIV-uninfected individuals to receive over six months of tuberculosis therapy (ten months, versus eight months, p < 0.001). Nevertheless, 7% of HIV-positive patients (13 of 196) who completed treatment experienced a relapse of their tuberculosis compared to just 1% (three of 362) HIV-negative patients. This difference was statistically significant (p < 0.001).
Because the HIV-positive patients had both clinical and sociodemographic characteristics that could have influenced the outcome of their tuberculosis therapy, the investigators performed further analyses to control for these potentially confounding factors. These analyses showed that being HIV-positive was independently associated with a risk of tuberculosis relapse (p = 0.003). The only other factor significantly associated with relapse was receiving intermittent as opposed to daily treatment (p = 0.004).
Overall, 85 HIV-positive patients died whilst taking anti-tuberculosis therapy or in the twelve months following its completion. This compared to 27 deaths amongst the HIV-negative patients. The investigators calculated that HIV-positive patients had a relative risk (RR) of death of 5.19 compared to HIV-uninfected patients, a statistically significant difference (p < 0.001).
HIV-positive patients who received potent anti-HIV therapy during the course of their tuberculosis therapy were protected against death (p = 0.01). Furthermore, patients who took effective HIV therapy converted their cultures faster (median 5 weeks versus 9 weeks, p = 0.03). The investigators also noted that none of the thirteen HIV-positive patients whose tuberculosis relapsed were taking potent antiretroviral therapy.
Significantly more HIV-positive patients (21%) experienced side-effects caused by anti-tuberculosis drugs than HIV-uninfected patients (12%, p < 0.005). However, taking anti-HIV treatment during tuberculosis therapy was not associated with an increased risk of side-effects.
The investigators then restricted their analyses to HIV-positive patients. They wished to see if duration of tuberculosis therapy amongst these patients was associated with the risk of relapse. They found a significantly higher rate of relapse amongst those patients who received six months of therapy (24 per 100 person years, five of 33 cases), versus those who received longer duration of treatment (7 per 100 person years, eight of 163 cases, p = 0.04).
Multivariate analysis showed that receiving six months tuberculosis therapy (p = 0.02) and intermittent dosing (p = 0.004), were significantly associated with treatment relapse in HIV-positive patients/
“We have shown HIV-infected patients with tuberculosis are significantly more likely to relapse after completion of a rifamycin-based regimen than HIV-uninfected/unknown patients”, write the investigators.
They add: “We have also shown that duration of tuberculosis treatment and intermittent dosing were strong independent predictors of relapse in HIV-infected patients.” They suggest that their finding that six months of tuberculosis therapy is associated with a higher risk of relapse is “new.”
“To our knowledge, a potential link between receiving HAART [highly active antiretroviral therapy] and lower risk of tuberculosis relapse has not been noted in the literature”, they comment.
There are potential interactions between antiretroviral and anti-tuberculosis drugs, as well as a risk of immune restoration illness if the two therapies are used together. Because of this, treatment guidelines recommend delaying the initiation of HIV therapy until the completion of tuberculosis treatment in patients with higher CD4 cell counts, or the initiation of HIV therapy after two months of tuberculosis treatment in patients with lower CD4 cell counts. The investigators acknowledge these recommendations, but write, “our results…provide compelling evidence to warrant the initiation of HAART during tuberculosis treatment in selected patients.”
An accompanying editorial notes that, given the emergence of extensively drug-resistant tuberculosis (XDR-TB) “it seems timely for a critical reappraisal” of treatment strategies recommending a similar duration of tuberculosis therapy in patients regardless of their HIV status.
Nahid P et al. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med 197: 1199 – 1206, 2007.
Perlman DC et al. Treatment of tuberculosis in HIV-infected patients: we need to know more. Am J Respir Crit Care Med 19: 1102 – 1103, 2007.