The mean survival time was 5.8 months and the incidence mortality rate was 9.9 per 10,000 PYs for early ART initiators compared to 5.5 new death rates per 10,000 persons–years for late ART initiators. There was also a statistically significant difference in mean CD4+ T cells between the cohorts and patients with late ART initiation had a better survival chance than patients with early ART initiation at all levels of time. Four randomized controlled trials have examined the question of the optimal timing of ART in TB/HIV co-infected patients. In 2010, the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT trial) demonstrated no overall difference in the primary endpoint of AIDS-defining illness or death between the early integrated therapy arm (ART commenced < 4 weeks of TB treatment) and late integrated therapy arm (ART commenced < 4 weeks after completing intensive TB treatment) . A second international multicenter randomized controlled trial, the AIDS Clinical Trials Group (ACTG 5221) study, reported that immediate ART (<2 weeks) did not reduce the primary endpoint of AIDS-defining illness or death compared with early ART (8 to 12 weeks) . However, both studies found that in patients with baseline CD4 counts < 50 cells/mm3, early ART initiation was associated with a significant reduction in AIDS or death. A third randomized controlled trial, the [Cambodian Early versus Late Introduction of Antiretrovirals] CAMELIA trial conducted in Cambodia, reported improved survival in predominantly pulmonary TB patients initiating ART at 2 weeks compared with 8 weeks .
In contrast, a Vietnamese randomized controlled trial of immediate (within 7 days of TB treatment) versus deferred (after 8 weeks TB treatment) ART initiation in patients with HIV-associated TB meningitis showed no survival benefit, and an increase in severe adverse events, in the immediate ART arm . Collectively, the results of these four trials suggest that ART should be started early in TB/HIV co-infected patients with advanced immunosuppression, apart from those with TB meningitis . The finding of the present study, however, differs from the above studies. The result of this study showed that initiating ART after two weeks (later) of starting TB therapy significantly increase survival among TB/HIV co-infected patients with newly diagnosed TB and with mean CD4+ T-cell counts of about 130 cells/mm3 compared with the initiation of ART before two weak (early). The difference of the current study from the previous findings could be explained by variation in the timing of ART initiation and study design. The high likelihood of drug-to-drug interaction, overlapping toxicities of TB and ART regimens, and the higher prevalence of immune reconstitution inflammatory syndrome (IRIS) during early initiation might be the contributing factors for the increased mortality.
Another plausible explanation for this discrepancy could be the cut-off point used in this study (two weeks), unlike the aforementioned trials that used different classification systems of ART initiation. This difference in the timing of ART initiation may affect the outcome of this study and may attribute to the differences observed in the present study and the other findings. The late ART initiation is too delayed in the previous studies, compared to the current study, and hence the patients may have a greater deterioration in their immunity in these studies and maybe a reason for the greater mortality.
The interactions between rifampin and the Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are particularly important because NNRTIs are recommended as components of initial ART in countries with a high burden of HIV infection . The concentrations of all of the available NNRTIs are significantly reduced because of CYP2B6 and CYP3A4 induction by rifampin . The effect of rifampin on nevirapine concentrations is greater than its effect on efavirenz concentrations. Reductions of 20%–55% in nevirapine concentrations have been reported [25,26], with a greater proportion of co-treated patients having trough levels of nevirapine below the target ranges [25,27,28]. Concomitant rifampin treatment results in reductions of ∼20%–25% in efavirenz peak and trough concentrations [29,30]. Among patients not receiving TB treatment, lower trough concentrations of efavirenz are associated with an increased risk of virological failure and selection of drug-resistant viral strains [31,32]. This drug interaction may be one of the causes that increase mortality at early ART initiation.
Most of the adverse effects due to the TB treatment and ART occurs within the first months of therapy . HIV-infected patients receiving TB treatment commonly experience drug toxicity [33,34]. Most studies suggest that adverse events are more common among HIV-infected patients than among HIV-uninfected patients being treated for TB. For example, a retrospective study of patients treated for TB in Canada found that HIV-infected patients were 3.8 times more likely to experience a significant drug-related adverse event (defined as one resulting in hospitalization or in modification or discontinuation of treatment) . Thus, due to overlapping toxicities of TB treatment and ART occur frequently, pushing discontinuation of therapy and increasing the risk of non-adherence. This is may also be one of the causes of increased mortality among patients with early ART initiation.
Paradoxically, IRIS occurs within 6 weeks of the initiation of ART but it has been reported to occur many months after the commencement of ART [36,37]. Data from retrospective and observational studies indicated that TB-associated IRIS occurs in approximately 11% to 71.4% of TB/HIV co-infected patients starting ART . Reports of high IRIS rates from various settings is a key reason for delaying the initiation of ART in patients receiving TB treatment [17,18,20]. This is maybe also another reason for the higher death during early ART initiation.
In this study, the majority of TB/HIV co-infected patients had a CD4+ T cell count of less than 250 cells/mm3. Most TB infections had occurred in those whose CD4+ cell count was < 250 cell/mm3. About twelve times as many patients with CD4+ T cells < 250 cells/mm3 were experiencing death compared to CD4+ T cells ³ 250 cells/mm3. These findings revealed that mortality upsurges as CD4+ T cells count decreases because the TB/HIV co-infection leads to severe immune suppression. Co-infection is associated with lower CD4+ T count than those with HIV alone, which could translate into an increased morbidity and progression of HIV to AIDS. Several other studies are consistent with this finding and they also pointed to the fact that CD4+ T cell count is lower among co-infected patients as compared to HIV infected alone and severe immune suppression is seen in those with CD4+ T cell count below 200 cells/mm3 [39,40]. Institutional based cross-sectional study conducted in Ethiopia on the magnitude and correlates of TB among HIV patients found that 79.5% of TB infection occurred in low CD4 level (< 200 cells/mm3), which could translate into increased morbidity, the progression of HIV to AIDS, and mortality .
Patients with ‘working’ baseline functional status were having an 84.9% of protection from death than patients with ‘bedridden’ baseline functional status, in which the former patients may have a better immunity status  and the later patients may present with an advance immunocompromised state and with many opportunistic infections.
The study has certain limitations. The investigators’ rely on the record-keeping of others, which has an effect in accurate comparison of the exposure and outcome. The investigators have also less control over variables including over exposure and outcome variables.