Can We Reduce HIV Reservoirs by Initiating ART at Acute Infection?
This report is part of a series of focused summaries from the “5th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies” held in St Maarten, December 6-9, 2011. Several presentations were given on the possibility to reduce HIV reservoirs by initiating ART at acute infection, including talks from Martin Markowitz, Jintanat Ananworanich, and Maria Buzon.
Acute HIV infection was the focus of an entire session at the 2011 HIV Persistence Workshop.
In his presentation, Martin Markowitz (Aaron Diamond Center, New York) updated the data from his one site trial comparing 3 versus 5-drug combination initiated at –or near- acute HIV infection. The 48 weeks data were initially presented last February at CROI, the 96 weeks data were available for the workshop.
Whether or not ART has been optimized with standard compact preferred 3-drug therapy remains a critical issue in HIV therapeutics, particularly as the field contemplates eradication strategies. This trial hypothesis was that targeting HIV entry, reverse transcription, integration and particle maturation via inhibition of HIV protease would result in improved virologic and immunologic outcomes when compared to standard 3-drug PI-based ART.
The design of the trial is shown in figure 1.
The primary endpoint was the percentage of subjects with plasma HIV-1 RNA below detection at week 48 using the single copy assay. In as-treated analysis, switch for tolerability was allowed. Patients detectable by standard assay at week 48 would be considered detectable in this analysis.
The authors calculated that the sample size should be of 22 patients in the 5-drug and 11 in the standard 3-drug arm to detect an approximate 50% treatment effect with 85% power at the 0.05 level of significance.
At 48 weeks, from 26 patients randomized in the 5-drug arm, 23 patients remained on study; and from 14 patients randomized to the 3-drug arm, 11 patients remained on study.
At 96 weeks, 18 patients remained on study in the 5-drug arm, and 10 patients in the 3-drug arm.
The baseline characteristic of patients is shown in figure 2.
As expected the 5-drug regimen achieved <50 copies/ml of plasma viremia faster (figure 3), but at week 48 there were 3 virological failures in the 5 drug arm, and none in the 3-drug arm.
Concerning these 3 cases of virologic failure in the 5-drug arm, 2/3 were detectable at week 36 and confirmed subsequently, 1/3 was below detection by week 12 with confirmed low level rebound at week 48.
-R5 virus at baseline
-TDF/FTC and ATZ/DRV susceptible virus at baseline
-no RAL mutations identified by consensus sequencing of the integrase coding region
-and were more than 95% adherent by history and random PI levels were consistent with dosing history elicited at the time of visit.
No differences were found in terms of viremia by using the single copy assay (figure 4).
The evolution of proviral DNA levels was also identical in the 2 arms (figures 5 and 6). No difference was even observed in decay characteristics.
Likewise, no difference was found for the decay of cell-associated HIV RNA at week 96 but the difference in median levels at week 96 favored the 5-drug arm (figure 7).
Finally, no difference in infectious virus titers was found (figure 8).
Overall, the virologic results are summarized in figure 9.
There were no statistically significant differences in the % of CD8+HLA+DR+ T cells at week 48 and levels of sCD14 in plasma at week 48 and 96 in suppressed HIV+ subjects treated with either 3- or 5-drug ART. This suggests that the early initiation of therapy may prevent residual immune activation that often accompanies treatment initiated later in the course of therapy, but is not influenced by the number of ARV in the combination beyond 3.
Difference in levels of activation between peripheral blood and GALT was more pronounced in the 5-drug arm (figure 10).
Overall, although there appeared to be some potential benefit of intensive early therapy, the effects appeared small and the results were quite disappointing. However, we have to keep in mind that this study enrolled rather early cases of infection than acute cases: mean 50 days after estimated date of infection.
In the study presented by Jintanat Ananworanich (Thai Red Cross AIDS Research Center, Bangkok), however, patients were treated in truly acute infection. This protocol, which continues to enrol subjects, allowed to diagnose very early acute infection and to treat patients within a few days (figure 11).
At the time of the presentation, data were available for the first 35 enrolled patients, with 12 at Fiebig I stage, 3 Fiebig 2, 17 Fiebig 3 and 3 Fiebig IV. Their mean CD4 cell count was 409 cells/mm3 (figure 12).
The ART regimens used were TDF/FTC/EFV in 13 patients and the same regimen + MRV and RAL in 22 patients.
The first interesting result concerned the HIV reservoir analysis before treatment initiation according to Fiebig stage. Interestingly, total HIV DNA in PBMC was significantly lower in Fiebig I versus Fiebig III at acute HIV infection (figure 13).
Then, they showed that the loss of CD4+CCR5+ T cells in sigmoid colon increases from Fiebig I to III. This loss occurred mainly in Central and Effector Memory subsets (figure 14).
After treatment initiation, rapid and equivalent plasma HIV RNA decline was observed with both mega-ART and ART regimens.
The percentage of CD4+CCR5+ T cells in sigmoid colon significantly increased after antiretroviral treatment in Fiebig III and IV subjects.
Total and integrated HIV DNA in PBMCs declined significantly after Mega-ART and ART. Total HIV DNA by week 24 was undetectable in 40% of patients. Integrated HIV DNA by week 24 was undetectable in 80% of patients.
Total and integrated HIV DNA in sigmoid colon declined significantly after Mega-ART. Total HIV DNA by week 24 was undetectable in 35% of patients. Integrated HIV DNA by week 24 was undetectable in 78% of patients.
The frequency of PBMCs harboring HIV DNA during Acute HIV predicted HIV reservoir size after 24 Weeks of treatment (figure 15).
Finally, when proviral DNA levels in PBMCs at 24 weeks of therapy were compared to those of patients treated a mean period of 56 months at chronic infection, they were significantly lower and closer to those of Elite Controllers (figure 16), demonstrating that a smaller reservoir size is obtained when ART is initiated at acute infection.
This protocol continues to enroll subjects and will evolve by testing:
-Therapeutic HIV vaccine in addition to early treatment followed by treatment interruption
-Drugs targeting HIV reservoir.
Maria Buzon (MGH, Boston) presented evidence that there was a reduction in HIV reservoir size after 10 years of ART started in primary infection. The "reservoir" here measured was integrated and total HIV DNA levels. In 9 patients treated at acute infection she performed longitudinal and cross-sectional comparisons with a cohort of 10 patients treated for 10 years at the chronic stage and 37 Elite Controllers followed for at least 8 years.
In acutely treated patients she observed a rapid decrease in total (figure 17a) and 2-LTR HIV-DNA after therapy initiation and very slow decrease of integrated HIV-1 DNA levels. A Better depletion of integrated and 2-LTR HIV DNA was found in patients initiating therapy during Fiebig III and IV.
The cross-sectional comparison showed that early treatment reduce total and integrated HIV DNA after 10 years of therapy to similar levels found in EC. However, they still demonstrated signs of recent infection events (2-LTRs) after long-term therapy.
Using viral reactivation assays, she also showed that early treatment reduced the functional reservoir to those levels observed in EC (figure 17b).
Key words: ART acute HIV, HIV cure workshop, HIV reservoirs, acute HIV infection