Two exciting presentations on the optimal time to start treatment were delivered by French researchers at the IAS conference in 2013.
The first paper was on how people who started treatment when their CD4s were above 500 achieved better reservoir depletion and T-cell count restoration. It was presented by Laurent Hocqueloux on behalf of the Coordinated Action on HIV Reservoirs.
This was the team who reported on the Visconti cohort — now called post-treatment controllers (PTCs). These are PLHIV who commenced treatment within four months of seroconverting then stopped completely after about 36 months and after an average of seven years off treatment still had undetectable viral loads and high levels of restored immune function. About 15% of the population are thought to be able to do this. To date, none of these PTCs need ART to control their HIV 1.
Off therapy, they are able to maintain and, in some cases, further reduce an extremely low viral reservoir 2. And this is despite the fact that none of them were genetically well-suited to control HIV progression.
This team also demonstrated in another group that very early treatment (within four months of seroconversion) drives down viral load to a level which indicates ‘deep depletion’ of HIV reservoirs: HIV-DNA of less than 2.3 log10 copies/106 peripheral blood mononuclear cells (PBMCs). The effect on HIV DNA was much more profound in those treated very early compared with those treated later in their HIV infection and in addition, HIV DNA continued to decline for over ten years of continuous treatment3.
However, the latest research this team reported at IAS 2013 involved PLHIV who started treatment later, known as the ‘chronic’ phase of infection. They wanted to compare how well people responded to treatment when they started at different CD4 counts.
Firstly, they decided what an ideal result would be and called this measure the optimal viro-immunological response (OVIR). Features of an OVIR are: restoration of CD4 cell count to greater than 900; a CD4/CD8 ratio greater than1; and HIV DNA reduced to less than 2.3 log10 copies/106 PBMCs (i.e., ‘deep depletion’ of viral reservoirs).
The participants in this study started treatment at three different CD4 counts: above 500; 200-499; and under 200. Only those who achieved and sustained an undetectable viral load (less than 50 copies) were included.
309 PLHIV were followed for a median of 3.7 years. The characteristics of those in the three CD4 ranges were similar: most of them were male under the age of 40 who started with a viral load between 40,000–200,000 copies/mL.
The study found that HIV DNA correlated negatively with CD4 count during treatment, that is lower HIV DNA was correlated with higher CD4 counts.
All participants responded well to treatment and at last study visit the following were the key immune-virological parameters for each range of starting CD4 count (respectively ≥ 500, 200-499, <200):
- last CD4 cells/mm³: 1011, 662, 515
- last CD4/CD8 ratio: 1.25, 0.88, 0.66 and
- last HIV DNA log10 copies/106 PBMCs: 2.51, 2.78. 2.91.
The percentage of people in each respective CD4 category (respectively ≥ 500, 200-499, <200) with:
- CD4 ≥900: 67%, 12% and 6%
- CD4/CD8 >1: 73%, 36% and 16% and
- HIV DNA <2.3 log10: 39%, 21% and 11%.
The percentage who met all three OVIR objectives (with CD4 ≥900) was 30%, 3% and 0%.
So, those who commenced treatment when their CD4 counts were above 500 were 56 times more likely to reach the study endpoint.
These impressive findings highlight the considerable benefit of starting treatment when CD4 counts are still relatively high, and conversely suggest that normal immune functioning is unlikely to be restored, even after very long periods of treatment, when delayed.
The authors suggest that PLHIV who commence treatment when their CD4 counts are high may be better candidates to benefit from a therapeutic vaccine against HIV and/or drugs which are designed to purge viral reservoirs; and thus be better set-up for any ‘functional cure' that may come along in the future.
Go to further details: study Abstract and presentation slides
The second presentation was made by Antoine Chéret on behalf of the OPTIPRIM trial team. Their rationale is that very early treatment with a potent and well-tolerated five-drug regime will reduce the HIV reservoir, better restore immune function and decrease inflammation and immune activation.
Their trial had two treatment arms: an optimised five-drug arm using darunavir/ritonavir + tenofovir + emtricitabine + raltegravir + maraviroc; and the control arm using darunavir/ritonavir + tenofovir + emtricitabine. The primary endpoint of the trial (at 24 months from treatment commencement) was HIV DNA log10 copies/106 PBMCs (which indicates greatly reduced HIV reservoirs.)
Other characteristics investigated were: changes in HIV viral load changes in CD4 cell counts and CD4/CD8 ratio; how well drugs were tolerated; HIV levels of HIV in semen and in rectal tissues; and changes in immune functioning.
The 90 trial participants were mainly gay men, median age 36, and almost all had symptoms of sero-conversion illness or another indication of acute HIV infection. The median length of infection was just 35 days, median VL was 250,000, median CD4 count was 472 and HIV DNA was 5.4 log10 copies/106 PBMCs.
By the 12-month mark, in both arms of the study, the percentage of participants achieving undetectable viral load had increased from 8% in the first month to 93%. CD4 counts rose to a median of 707 and the median CD4/CD8 ration was now 1.13. In terms of HIV genetic material in blood, HIV DNA had fallen about 22-fold; 25% of participants had decreases greater than 2.0 log10 copies/106 PBMCs; and 51% had less than 200 copies/106 PBMCs indicating very low levels of HIV integrated into their key immune cells.
The study team concluded that very early commencement of HAART has a profound impact on HIV reservoirs and leads to better immune restoration compared to commencing treatment during later stages of HIV. They suggested that the immune benefits seen at 12 months probably reflect early protection of memory T-cells and a reduced HIV reservoir.
In this study adherence was well maintained and tolerance of the treatment very good. This is good news for those PLHIV who are diagnosed very early, and suggests that by treating early, immune function can be preserved and HIV seeding into reservoirs reduced, again suggesting that such people may benefit from therapeutic vaccines and future attempts to flush out their HIV reservoirs.
Go to further details: study Abstract and selected presentation slides
Recent research out of the Options Project in San Francisco General Hospital reached the same sort of conclusions. In this study, PLHIV who had been diagnosed within six months of infection and treated immediately had significantly lower T-cell activation, a 4.8-fold lower HIV-DNA level and lower cell-associated HIV-RNA, compared to those who delayed treatment.
The authors suggest that the extended high levels of HIV in untreated people prior to treatment may result in higher ongoing damaging immune activation and inflammation. Extended HIV replication before treatment may establish an irreversible pro-inflammatory environment, perhaps by damaging gut tissues or by establishing more active cycles of HIV replication 4.
Taken together, these two IAS presentations provide support for the benefits of treatment both very early in HIV infection or before CD4 cell counts have fallen below 500. In the current Australian context where more regular and frequent testing is being recommended for people at risk, and particularly sexually active gay men, this research is suggesting that if people find that they have been infected with HIV, there are considerable long-term benefits in treating as soon as possible.
- Sáez-Cirión A et al. for ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013 Mar;9(3):e1003211. Full-text: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat...
- Graf EH, O'Doherty U. Quantitation of integrated proviral DNA in viral reservoirs. Curr Opin HIV AIDS. 2013 Mar;8(2):100-5. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/23340051
- Hocqueloux L et al. for AC32 (Coordinated Action on HIV Reservoirs) of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS). Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T-cell counts. J Antimicrob Chemother. 2013 May;68(5):1169-78. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/23335199
- Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H et al. Antiretroviral Therapy Initiated within Six Months of HIV Infection is Associated with Lower T-cell Activation and Smaller HIV Reservoir Size. J Infect Dis. 2013 Jul 16. doi: 10.1093/infdis/jit311 Abstract:http://www.ncbi.nlm.nih.gov/pubmed/23852127