IAS 2013: Intensive ART During Primary HIV Infection Lowers Viral Reservoir

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Starting intensive antiretroviral therapy (ART) with a 5-drug regimen during the earliest stages of HIV infection can result in lower levels of virus in resting T-cell reservoirs, leading to improved immune function and potentially a better chance at a functional cure, according to studies presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this month in Kuala Lumpur.

One of the major barriers to eradication of HIV is that it rapidly establishes itself in long-lived resting T-cells. The virus can hide here indefinitely while a person is on ART, but can "wake up" when host cell are activated and begin replicating if antiretrovirals are stopped. Studies have shown that reservoir "seeding" begins soon after initial HIV infection, accompanied by immune activation, but very early treatment may be able to interrupt this process.

OPTIPRIM

Antoine Chéret and fellow investigators with the French OPTIPRIM (ANRS147) study are following a cohort of 90 people randomly assigned to start either a standard 3-drug ART regimen or an intensive 5-drug regimen during early HIV infection.

Most participants were men, with a median age of about 36 years and a median CD4 T-cell count of 472 cells/mm3. The median time from estimated date of infection was 35 days, almost all (97%) had symptomatic primary HIV infection, and 43% were classified as having acute infection (minimal Western blot reactivity).

The standard ART regimen consisted of boosted darunavir (Prezista) plus tenofovir/emtricitabine (the drugs in Truvada), while the intensive regimen also added the integrase inhibitor raltegravir (Isentress) and the CCR5 blocker maraviroc (Selzentry) -- a total of 4 antiretroviral classes. Treatment is scheduled to continue for 2 years, at which point participants will interrupt therapy to see if they can maintain viral control like those in the VISCONTI cohort.

Treatment is still ongoing, but Chéret presented data for the first year. Adherence was good and treatment was generally safe and well-tolerated, with just 2 serious adverse events (lipodystrophy and pancreatitis) in the 3-drug arm. Most participants achieved undetectable plasma HIV RNA, rising from 8% after 1 month to 50% at 3 months to 93% at 12 months.

They also showed decreased HIV DNA in peripheral blood mononuclear cells (PBMCs), indicating a reduced viral reservoir in T-cells. The median decline was 1.43 log copies per million PBMCs, with 25% experiencing more than a 2-log decrease. Lower plasma HIV RNA and HIV DNA in PBMCs at baseline were significant predictors of greater reduction in HIV DNA at month 12.

The median CD4 count rose by 235 cells/mm3 and the CD4/CD8 ratio normalized. Furthermore, patients did not show the same degree of reduction in naive and central memory T-cells in favor of more differentiated cell types, as seen in people treated during chronic infection, leading the investigators to suggest that early ART protected long-lived memory cell types.

"Despite the viro-immunological storm during primary-infection, treatment initiation at this stage is effective within the first 3 months to reduce plasma and cellular HIV loads," the OPTIPRIM researchers concluded. "Treating patients at the earliest time in primary infection induce[s] a strong decrease of HIV reservoirs, and might increase likelihood for post-treatment control."

New Era

In a related poster presentation, Eva Wolf and fellow investigators with the German New Era study described findings to date from an ongoing 7-year clinical trial (begun in 2009) evaluating multi-class ART during primary and chronic HIV infection.

The analysis included 20 patients who started treatment during primary infection (within 3 weeks of diagnosis) using a protease inhibitor, 2 NRTIs, raltegravir, and maraviroc. Another 20 people with chronic infection who had been on suppressive protease inhibitor-based ART for at least 3 years added raltegravir and maraviroc.

In this study, cell-associated HIV DNA decreased significantly during the first 2 years of treatment in the primary infection group, but remained more or less stable in the chronic infection group after intensifying therapy. At 24 months, median proviral DNA -- that is, viral reservoir -- levels were significantly lower in people who started treatment during primary infection. In addition, people who started ART earlier were significantly more likely to have a near-normal CD4/CD8 ratio (90% vs 35%).

"[Primary HIV infection] patients receiving early treatment with multi-drug-class HAART achieved lower cell-associated HIV DNA levels and a better immune reconstitution than chronically infected patients on intensified long-term suppressive HAART," the researchers concluded.

Both OPTIPRIM and New Era results to date indicate that treatment during primary infection lowers reservoir HIV DNA, but do not show if intensified ART is necessary, or whether standard regimens started early enough might have a similar effect.

SPARTAC

James Williams from the University of Oxford gave a late-breaker presentation of data from SPARTAC, a larger trial of a short course of ART started during primary HIV infection (here defined as within 6 months since seroconversion).

Participants were randomly assigned to receive either no early treatment or a standard 3-drug ART regimen for either 12 or 48 weeks.

The main trial, which included more than 350 people in 8 countries, found that 48 weeks of ART initiated during primary infection -- but not 12 weeks -- could significantly delay disease progression and viral rebound, but rebound did occur not long after stopping therapy.

At the IAS meeting, Williams presented data from a subgroup of 40 male SPARTAC participants in the U.K. who started early ART. Again, the researchers found that people who received either 12 or 48 weeks of early therapy experienced significant decreases in cell-associated HIV DNA.

Pre-treatment levels of HIV RNA in plasma and HIV DNA in PBMCs were strongly correlated with each other, and lower levels prior to treatment were associated with longer delay to viral rebound. However, plasma viral load and HIV DNA levels were not determined by estimated time since seroconversion, the researchers concluded, nor was there evidence to suggest that "proviral load" is associated with time to viral rebound.

Total and integrated DNA levels were "significant predictors of disease progression," Williams told reporters at a press conference prior to his presentation. "This confirms the role of the HIV reservoir in HIV pathogenesis and its importance in a functional cure."

7/24/13

References

A Chéret, G Nembot, V Avettand-fenoël, et al. Impact of 12 months HAART on cell-associated HIV-DNA in acute primary HIV-1 infection in the OPTIPRIM-ANRS 147 trial. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WEAB0101.

E Wolf, J Bogner, C Hoffmann, et al. 5-drug HAART during primary HIV infection leads to a reduction of proviral DNA levels in comparison to levels achievable during chronic infection. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract MOPE097.

JP Williams, J Hurst, N Robinson, J Frater, et al. HIV-1 DNA levels after antiretroviral therapy in primary infection predict disease progression: the SPARTAC Trial. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WELBA04.