HAART reduces risk of death or new AIDS in HIV patients with TB

Highly active antiretroviral therapy (HAART) significantly reduces the risk of new AIDS-defining illness or death in HIV-positive individuals coinfected with tuberculosis (TB), according to a United Kingdom-based study published in the November 1^st edition of the Journal of Infectious Diseases (now available on-line).

The investigators, from London’s Royal Free Hospital and University College London Medical School, compared morbidity rates in TB patients before and after HAART became available in 1996, also found the risk of new AIDS defining illness and death occurring was greatest during the first two months of TB, particularly for individuals with a CD4 cell count below 100 cells/mm³, even in the HAART era.

These findings could have important implications for HIV/TB treatment strategies, as concerns about the risk of drug interactions, immune reconstitution illness, and high pill burden often mean that doctors delay starting HAART in patients with a CD4 cell count below 200 cells/mm³ until two months of TB therapy have been taken. There are potential risks in this approach, however, as patients could experience further disease progression before HAART is started or has had time to improve the immune system.

From a retrospective review of medical records, investigators identified a total of 96 HIV-positive patients who had a confirmed TB diagnosis between 1988 and 2001. Individuals were divided into two groups depending on whether their TB was diagnosed in the pre-HAART era (before 1996, 36 patients), or the HAART era (1996 onwards, 60 individuals). Patients in whom TB was diagnosed after 1996 were older (median age 35 years versus 30 years, p = 0.004), less likely to be male (55% versus 83%, p = 0.005), more likely to be non-white (p = 0.40), and heterosexual (68% versus 47%), reflecting the changing demographics of HIV in the UK. CD4 cell counts at TB diagnosis were comparable in the pre-HAART and HAART eras.

Follow-up was provided for a median of 3.6 years, and during this time 30 deaths occurred, 18 before 1996 and twelve in the HAART era. Deaths occurred a median of 1.8 years after the commencement of TB treatment. Patients in whom TB was diagnosed prior to 1996 had an increased risk of death (p = 0.012), and the cumulative risk of death after one year was 20% for the pre-HAART patients, compared to 10% for the HAART era patients. The four year risk of death was 43% for the pre-HAART patients and 22% for patients diagnosed with TB after 1996.

In the pre-HAART era six deaths were caused by opportunistic infections, five by AIDS-related cancers, with the cause of death in seven cases being unknown. After 1996 four deaths were due to opportunistic infections, three individuals died because of HIV-related cancers, one patient died because of heart problems, two individuals died of hypothermia after drug or alcohol use, and two causes of death were unknown.

New AIDS-defining illnesses were diagnosed in a total of 22 pre-HAART patients and 20 patients in the post-1996 group. These illnesses developed a median of 0.4 years after TB therapy was initiated. The risk of new a new AIDS event or death was significantly higher for patients diagnosed with TB in the pre-HAART period (p = 0.023), and the cumulative one year risk of an AIDS-defining event in the pre-HAART patients was 40% compared to 34% for the post-1996 patients. The cumulative four-year risk of a new AIDS-defining event was 69% for patients in whom TB was diagnosed prior to 1996 and 43% for patients with TB after HAART became available.

The risk of death was reduced by 60% for the HAART era patients (hazard ratio [HR] 0.40, p = 0.014). The investigators also established that patients who had a low CD4 cell count at the time of TB diagnosis (or for whom data on CD4 cell count at this time were lacking) were also at increased risk of death. In particular, the investigators noted that the risk of death was greatest for patients with a CD4 cell count below 100 cells/mm³ at the time of TB diagnosis (HR 3.42). Patients who had a previous AIDS-defining illness were also at greater risk of death (HR 2.58). The relationship between baseline CD4 cell count and the risk of death was strengthened after the investigators adjusted for time period.

In further analysis, the investigators noted that the risk of a new AIDS-defining illness or death was particularly high during the first two months of TB treatment. Although the investigators found that this risk was present in both the pre- and post-1996 eras, the risk was particularly significant for patients diagnosed with TB before HAART became available (p = 0.027). In addition, the investigators established that the risk of new AIDS or death was higher for patients with a CD4 cell count below 100 cells/mm³ (p = 0.001). Of the 15 patients who died or had a new AIDS-defining diagnosis in the first two months of TB treatment, eleven (73%) had a CD4 cell count below 100 cells/mm³ (median 50 cells/mm³).

As expected, HAART use was associated with a marked decrease in the risk of death or a new AIDS-defining event (HR 0.38).

TB therapy continued for a median of 35 weeks. Side-effects severe enough to warrant the discontinuation of TB treatment developed in 11% of patients treated before 1996 and 12% of individuals treated in the HAART era. A total of six patients treated for TB after 1996 developed a paradoxical reaction (25% of all patients treated for TB after 1996 with a CD4 cell count below 100 cells/mm³). These reactions occurred between 15 and 30 days after starting HAART, and patients had a median baseline CD4 cell count of 40 cells/mm³.

“We have reported outcomes in patients coinfected with TB and HIV who were treated before and during the HAART era. When the effect of HAART was examined directly, it was found to be associated with marked reductions in the risk of death and new AIDS-defining illnesses”, write the investigators, adding, “although complications of treatment – such as drug interactions, drug toxicity, and paradoxical reactions – did arise, they did not translate into compromised survival for coinfected patients receiving HAART.”

The investigators stress the high rates of new AIDS-defining illness and death observed during the first two months of TB treatment, particularly in patients with a CD4 cell count below 100 cells/mm³. Further, the investigators stress that the risk of further disease progression was high for severely immune suppressed patients during the first two months, even during the HAART era.

Fears about the development of immune reconstitution syndrome and concerns about adherence often mean that doctors delay initiating HAART in patients with a CD4 cell count below 100 cells/mm³ until patients coinfected with TB have completed the first two months of TB therapy. The investigators note, “our data suggest that the deferment of HAART in this subgroup is at the expense of a significant risk of death and new AIDS-defining illnesses during the early period.”