Tuberculosis (TB) is the most common infectious cause of death in HIV patients. The question as to when to start antiretroviral therapy (ART) in such patients with TB remains unanswered. Early initiation of ART may be associated with clinical deterioration related to the immune reconstitution inflammatory syndrome (IRIS), with toxic effects of drugs, drug interactions, and a high pill burden, whilst a delay in initiating ART may result in AIDS-related illness and death. Current guidelines recommend that ART be initiated 2 to 8 weeks after the initiation of TB therapy in all patients with HIV-associated TB. Three studies published in the New England Journal of Medicine have sought to address the question of optimal timing for the initiation of ART.

The first study, CAMELIA (Cambodian Early versus Late Introduction of Antiretrovirals), tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed TB and CD4+ T-cell counts ≤200/mm3.. After beginning the standard, 6-month treatment for TB, 661 patients (median CD4+ T-cells 25/mm3 and median viral load5.64 log10 copies/ml) enrolled from five hospitals in Cambodia, were randomised to treatment (2 weeks after beginning TB treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival.

The study reported the following findings after a median follow up of 25 months:

• The risk of death was reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), vs. 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% CI; 0.44 to 0.86; p = 0.006).

• The risk of TB-associated immune reconstitution inflammatory syndrome was increased in the earlier-ART group (2.51;, 1.78 to 3.59; p <0.001).

• Irrespective of the study group, the median gain in the CD4+ T-cell count was 114/mm3and the viral load was undetectable at week 50 in 96.5% of the patients.

This study concluded that initiating ART 2 weeks after the start of TB treatment improved survival among HIV-infected adults with CD4+ T-cell counts ≤200/mm3

The open label AIDS Clinical Trials Group Study A5221 compared earlier ART (within 2 weeks after initiation of TB treatment) with later ART (between 8 and 12 weeks after start TB treatment) in 809 HIV patients across 4 continents with suspected TB, who had CD4+ T-cell counts <250/mm3 (median at baseline 77/ mm3) and HIV-1 RNA level of 5.43 log10 copies/ml. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) AIDS–defining illness at 48 weeks.

The following finings were noted:

• In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks vs. 16.1% in the later-ART group (95% CI, −1.8 to 8.1; p = 0.45).

• Among patients with screening CD4+ T-cell counts <50/ mm3, 15.5% of patients in the earlier-ART group vs. 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; p = 0.02).

• TB associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, p = 0.002).

• The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (p=0.38).

This study concluded overall that earlier ART did not reduce the rate of new AIDS-defining illness and death compared with later ART, but there was lower rate in those with CD4+ T-cell counts < 50/mm3.

The third study conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) had an open-label, randomised, controlled design, and involved 642 ambulatory HIV patients with TB (CD4+ T-cells <500/mm3). At baseline, the median CD4+ T-cell count was 150/mm3 and the median viral load was 161,000 copies/ml, with no significant differences between the two groups. The patients were assigned to the earlier-ART group (initiated within 4 weeks after start of TB treatment, n= 214) and later-ART group (initiated during first 4 weeks of continuation phase of TB treatment, n= 215).

The following findings were reported:

• The incidence rate of AIDS or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) vs. 7.8 per 100 person-years (19 cases) in the later-ART group (incidence-rate ratio, 0.89; 95% CI, 0.44 to 1.79; p = 0.73).

• Among patients with CD4+ T-cell counts<50/mm3, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 0.07 to 1.13; p = 0.06).

• The incidence rates of the IRIS were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 1.48 to 4.82; p<0.001).

• Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (p = 0.006).

The researchers conclude that early initiation of ART in patients with CD4+ T-cell counts <50 per/mm3 increased AIDS-free survival, whilst delaying the start of ART to the first 4 weeks of the continuation phase of TB treatment in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death.

According to an editorial, these studies provide important evidence to guide clinicians treating patients with HIV-associated TB by showing that earlier initiation of ART appears to be beneficial in patients with TB in whom immunosuppression is advanced, but this benefit is at the expense of an increase in the risks of IRIS and of adverse events that lead to the switching of ART drugs. However, in patients with higher CD4+ T-cell counts, the authors suggest that “the benefit of early ART is less clear, and it may be reasonable to delay ART until the continuation phase of TB treatment in order to simplify treatment and reduce the risk of complications.” The note one caveat to these findings being that the majority of the patients had pulmonary TB which has a reasonably good prognosis, in the absence of drug resistance; IRIS in this group is rarely life-threatening, but in those with more severe forms of disease, such as TB meningitis, mortality is much higher and intracranial IRIS may prove fatal. Therefore, the optimal time to initiate ART in patients with HIV-associated TB may depend not only on the degree of immunosuppression but also on the site of disease.

The editorial also discusses a number of practical issues to consider when treating such patients outside of research settings, such as the difficulty in diagnosing TB in this patient population, the high pill burden associated with treatment with multiple antiTB drugs, ART, and antimicrobial prophylaxis, as well as possible drug interactions and adverse effects,. Treatment may also be complicated by the need to treat multidrug-resistant or extensively drug-resistant TB, drug-resistant HIV infection, or both, which would require even more complex regimens that may be less well tolerated. The authors conclude nevertheless that “despite these caveats, these data provide support for the earlier initiation of ART in patients coinfected with HIV and TB who have advanced immunosuppression, apart from those who present with tuberculous meningitis.”