Iranian and Argentinean researchers presented contradictory evidence on the risks of delaying antiretroviral therapy in people receiving TB treatment at the XVII International AIDS Conference in Mexico City, during a poster discussion on TB and HIV.
The two studies showed conflicting results – an Iranian cohort finding a significant survival benefit and lessened morbidity with earlier ART, and an Argentinian cohort linking earlier ART to worse overall survival. However, significant clinical differences between the Argentinian patient groups make interpretation of their findings highly uncertain.
Determining the right time to initiate ART in people receiving treatment for active TB has been controversial for several reasons.
The first is due to the concern that rapid immune reconstitution in patients still in the early stages of TB treatment may result in a fierce immune reconstitution inflammatory syndrome as the immune system reacts to still plentiful TB antigen to produce a harmful inflammatory reaction. That fear was put to rest by a study published in 2007 by Stephen Lawn and colleagues from South Africa, showing a low risk of death from TB IRIS in the first few months of treatment if people with TB received immediate treatment.
That study also showed a higher risk of death among people with low CD4 counts who delayed antiretroviral treatment after a TB diagnosis.
However, the second concern – that of drug interactions between rifampicin and nevirapine – remains widespread due to the lack of availability in some settings of the alternative NNRTI, efavirenz, which is recommended for use while people are taking efavirenz. Another South African study, presented at last year’s World Lung Health conference and published this week in the Journal of the American Medical Association, shows that people who took rifampicin alongside nevirapine had twice the risk of viral load rebound when compared to those who took efavirenz with rifampicin.
A third concern is the potentially increased risk of hepatotoxicity when antiretroviral therapy is used alongside TB treatment.
Iran
Payam Tabarsi of the Mycobacteriology Research Center, Tehran, presented a retrospective chart review of TB treatment outcomes among 69 HIV/TB co-infected patients hospitalised in Masih Daneshvari Hospital, Tehran, Iran between 2002 and 2007. Their results showed sixfold greater rates of mortality in those who began ART eight weeks, as compared to two weeks, after initiating TB treatment.
Group I ("late treatment") included 47 patients treated between 2002 and 2005, in whom HAART was initiated after 8 weeks of TB treatment for those whose CD4 cell count was less than 200 cells/mm3. Group II ("early treatment") included 22 patients treated between 2005 and 2007, in whom ART was initiated after 2 weeks of TB treatment if CD4 cell counts were less than 100 cells/mm3, and 8 weeks after initiation of TB treatment if CD4 cell counts were in the range from 101 to 200 cells/mm3.
Outcomes of interest included hepatotoxicity, response to TB treatment, immune reconstitution syndrome (IRIS) and new opportunistic infections.
Baseline characteristics were similar in the late-treatment and early-treatment groups: both were largely male, with no prior OI diagnoses, largely HCV-positive (80.9% vs. 68.2%; p=non-significant [ns]), and with similar rates of TB drug resistance (6.4% vs. 4.5% MDR, respectively). The early-treatment group was slightly older (mean age, 37.8 versus 33.3 years, p=.015). The initial ART regimens used in each group, however, were completely distinct: the late-treatment group received the nelfinavir-based regimen in use at that time, and the early-treatment group received an efavirenz-based regimen.
Serious (grade 3 or 4) adverse drug reactions were seen with comparable frequency in the late-treatment and the early-treatment group (8.5% vs. 9%, p=ns), as were immune reconstitution syndrome (12.7% vs. 10.7%, p=ns) and new opportunistic infections (17.0% vs. 9.1%, p=ns).
Overall mortality rates, however, were more than sixfold higher in the late-treatment group than in the early-treatment group (27.7% vs. 4.5%, p=0.028). TB cure rates were nearly twice as high with early treatment (86.4% vs. 46.8%, p=.002), and TB treatment failure rates were lower, although not statistically significant (9.1% vs. 25.5%, p=0.198).
Tabarsi concluded that "early initiation of HAART in TB/HIV patients, especially in those with more advanced immunodeficiency due to HIV infection, may be practical to implement, and decreases mortality in these patients without significantly contributing to increased toxicity."
Argentina
Conversely, results from a multisite Argentinian study showed higher mortality rates in HIV/TB co-infected patients who received earlier ART. However, mortality specifically due to TB was not affected, and significant differences between the study groups (including significantly worse clinical history in the early-treated group) leaves these findings highly questionable. The poster was presented by Javier Jose Toibaro of Hospital J. M. Ramos Mejia in Buenos Aires, Argentina.
In this study, clinical outcomes were compared between co-infected patients who started ART treatment eight weeks ("early") or after eight weeks ("late") of initiating their TB treatment. Data was drawn from a group of 142 patients across twelve sites in Argentina between January 1997 and January 2008.
There were 69 patients in the early ART group and 73 in the late HAART group. There were no significant differences between the treatment groups in terms of sex (early group, 60% male, late group, 87% male, p=0.41), age (mean, 38 years), median baseline CD4 cell count (78 cells/mm3 in both groups), rates of disseminated TB (roughly 34% in each group), injection drug use, or body mass index.
However, the earlier ART group had higher rates of both prior TB diagnoses (29.4% vs. 8.2%, p=.0012) and prior AIDS diagnoses (33.3% vs. 17.8%, p=.033). There was also a significantly higher rate of concomitant HIV/TB diagnosis in the late-treated group (52% vs. 24.6%; p=.0008).
There was no significant difference in post-TB treatment median CD4 cell counts (174 cells/mm3 for early treatment vs. 190 cells/mm3 for late treatment, p=0.71). Nor was there any difference in TB-associated mortality (40% in both groups),
However, overall (all-cause) mortality rates were actually higher for the earlier-treated group (14.4% vs. 6.8%, p=.013). Rates of TB treatment completion and cure were also higher for the later-ART group (87.8% vs. 70.7%, p=.035).
While these findings appear to contradict the benefits of earlier HAART found in the Iranian and other studies, the researchers stressed that the differing factors between the treatment groups could easily confound the results. In particular, the significantly worse clinical histories of TB and clinical AIDS in the early-treated group – who might otherwise have been expected to perform better – would worsen their prognoses.
Toibaro concluded that, due to these differences, "further investigations are required to clarify these findings."
References:
Tabarsi P et al. Early initiation of antiretroviral therapy results in decreased morbidity and mortality among patients with advanced HIV disease. Seventeenth International AIDS Conference, Mexico City, abstract MOPDB205, 2008.
Toibara JJ et al. Early versus late cART treatment in HIV/TB co-infected patients in Argentina. Seventeenth International AIDS Conference, Mexico City, abstract MOPDB206, 2008.