This trial was conducted to gain more evidence regarding the ideal timing of initiation of ART in late presenting HIV positive patients who present with either PCP oder TE.
The major strength of this study is that it provides data for the important question when to start ART in a very vulnerable group of HIV-infected patients with two common opportunistic infections.
The protease-inhibitor (PI) atazanavir/ritonavir (ATV/r) was chosen as core agent, recommended in several both national and international guidelines at the time of study planning and initiation 2010–2011 (WHO, EACS, CDC) [1, 30, 31]. ATV/r was chosen as a once daily (at this time) state of the art regimen, as it has a higher genetic barrier compared to e.g. efavirenz and causes a rapid decline in viral load [32]. Retrospectively seen, this choice probably contributed to the low recruitment, as possible drug–drug interactions.
In general, the study medication was well tolerated, most adverse events were mild. There were no unsuspected adverse events related to the study medication. Only few adverse events were severe adverse events and only few drop-outs occurred. The total number of these events (drop-out, AE grade 4, SAE) were equally low in both treatment groups, considering the severity of the underlying condition.
A review of the available literature regarding timing of ART in HIV positive patients with opportunistic infections was performed. To our knowledge only one randomized clinical trial, performed by the AIDS Clinical Trial Group (ACTG 5164) seems similar and comparable to our study population and setting [22]. In this trial a total of 282 subjects (39 sites within the United states and Johannesburg, South Africa) were randomized to initiate ART immediately or after OI treatment. The study provided lopinavir/ritonavir [LPV/r], emtricitabine [FTC], tenofovir disoproxil fumarate [TDF], and stavudine [d4T]. However, any antiretroviral agent approved by the FDA for the initial treatment of HIV was allowed. A boosted PI with two NRTIs was used in 89% of subjects in the immediate arm and 85% of subjects in the deferred arm while NNRTI-based regimens with two nRTIs were used in 11% and 16%, respectively.
There was no statistically significant difference in the primary endpoint and both arms achieved similar CD4 T-cell counts and viral load declines by week 24. Importantly, the immediate arm had fewer deaths/AIDS progressions (p = 0.035), longer time to death/AIDS progression (stratified HR = 0.53, p = 0.02), and shorter time to achieving an increase in CD4 T-cell counts to > 100/μL (11.8 versus 4.2 weeks). The authors concluded that, although there was no significant difference between immediate and deferred ART in the primary endpoint (clinical and virologic response), immediate ART reduces death/AIDS progression over 48 weeks. However, there are major differences in the study settings to our trial because different antiretroviral regimens have been used and heterogeneous opportunistic infections were allowed. The initiation of ART in the immediate arm was 12 days, compared to 45 days in the deferred arm. To get better comparability, we’ve chosen a defined ART regimen with boosted Atazanavir as the third agent. This was an appropriate, frequently recommended and used regimen at time of study planning 2010–2011 [30, 33]. We focused on the two most frequently occurring OI in high income countries, which is another strength of this study.
This study shows no evidence that an immediate antiretroviral combination treatment with ATV/r and 2 NRTIs (TDF/FTC) in patients with an acute AIDS-defining opportunistic infection (toxoplasmosis or pneumocystis pneumonia) has any positive or negative effect on the overall outcome of patients with advanced HIV-related immunosuppression (CDC class C). The primary endpoint ‘clinical progression’ (including death, all new or relapsing OI, and other G4 clinical endpoints within 24 weeks) occurred equally in both treatment arms. Secondary endpoints as hospitalization days after completion of OI treatment, incidence of IRIS, virologic outcome at week 24 were also distributed equally in each treatment group. There were also no significant differences in self-reported bodily or psychological well-being using the SF36 body score and SF36 psychological score questionnaire between the two treatment groups.
Other trials with different study populations, mostly in resource poor countries and with different OI (like tuberculosis, cryptococcal meningitis) showed worse outcomes, if ART was initiated sooner, compared to deferred initiation [26, 28, 29].
The overall message regarding those OI (tuberculosis and cryptococcosis) was, not to defer ART at low CD4 cell counts, unless patients are suffering from neurologic affection, especially cryptococcal meningitis [34,35,36,37].
However, some further limitations deserve to be mentioned. Due to the small size of the two treatment groups, minor differences in primary and secondary endpoints of incidence rates of SAE might not have been detectable.
Another limitation is the fact, that nowadays a majority of patients is treated with an integrase inhibitor as the core agent in first-line ART. Data from the IDEAL trial probably cannot be applied for this treatment selection, because the incidence of treatment-associated immunological reconstitution might be higher with integrase inhibitors (INI). Therefore, it would be necessary to run another trial using INI as the core agent.
Furthermore, epidemiology, diagnostics and therapy in both PCP and TE are evolving, possibly leading to limitations in transferring the results to current populations [38, 39].
Despite a multicenter approach with much effort in 16 German HIV care experienced study centers only 61 of the planned 210 patients could get enrolled into the study. For the most part, in our opinion this was caused by the severity of the underlying condition (e.g. neurological alterations due cerebral toxoplasmosis, patients in critical conditions on intensive care units (e.g. patients couldn’t give informed consent in the short time period, which was mandatory for inclusion into the study). Additionally, difficulties occurred due to multiple potential drug interactions due to supportive drugs. E.g. ATV/r and proton pump inhibitors, often used in critical care patients, couldn’t be coadministered. These difficulties should be considered in the planning of potential future early treatment evaluation trials with novel integrase-based HIV regimens, that have fewer side effects.