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Getting Closer to a Functional Cure?

, by Reilly O'Neal

Less than two weeks after the revelation that an infant may have experienced a “functional” cure following extremely early HIV treatment, researchers with the French VISCONTI study report that 14 adults also treated early have achieved long-term control of the virus after stopping HIV therapy.

“Emerging evidence shows that early treatment has long-term benefits,” note Asier Sáez-Cirión of France’s Pasteur Institute and colleagues. These benefits include decreased HIV replication, better-preserved immune function, and reduced viral reservoirs—sources of “hidden” virus, unreachable by antiretroviral drugs, which pose a major obstacle to curing HIV infection.

These advantages diminish when antiretroviral treatment is interrupted, Sáez-Cirión and colleagues write, but his team has identified individuals “in whom the viral load remains undetectable for several years after the interruption of prolonged therapy that was initiated very early after infection.” Nicknamed “post-treatment controllers” or PTCs, “these individuals hold important clues in the search for a functional HIV cure”—that is, a cure that does not eradicate HIV from the body but keeps it suppressed without lifelong drug therapy.

The VISCONTI Study

Sáez-Cirión and colleagues analyzed data on 14 post-treatment controllers in the French VISCONTI cohort. These ten men and four women were diagnosed with HIV within roughly two months following infection, during the acute or primary phase. All received standard antiretroviral therapy and saw their viral load become undetectable within 0.5 to 8 months; the median, or midpoint, of this range was 3 months. The median duration of antiretroviral treatment was roughly three years (36.5 months).

Following treatment interruption, control of the virus lasted for a median of 89 months (more than seven years), and CD4 cell counts remained stable. “Eight PTCs had viral loads below the detection limit in all available samples after treatment interruption,” the authors note, “whereas occasional increases were recorded for the other six patients.”

The researchers report that certain genetic features and aspects of their cells’ response to HIV distinguish these individuals from “elite controllers,” a small population of people whose immune systems are able to keep HIV in check without treatment. Also, PTCs in this study “had a more severe primary infection with higher viral loads and were frequently symptomatic,” the authors observe, “which may have prompted the early treatment in some cases.”

But like elite controllers, PTCs in the VISCONTI study displayed very low HIV reservoirs, as indicated by the presence of HIV’s genetic material (DNA) in samples of blood cells. In the six PTCs for whom HIV DNA levels could be tracked since primary HIV infection, those levels had declined sharply at the start of or just before treatment interruption. HIV DNA levels could be followed sequentially after HIV meds were stopped in eight individuals. In five of these persons, HIV DNA levels progressively declined over the years in the absence of treatment, and in two, HIV DNA levels remained stable. (By contrast, levels actually rose in one individual whose HIV infection stemmed from a “blood exposure accident” and who, the authors note, had “detectable viral replication at low levels in the last few years.”)

In addition, the type of cells involved in the viral reservoir was unusual in this study. Particularly interesting is that only a minimal proportion of cells in the total viral reservoir were longer-lived types of resting CD4 cells (that is, CD4 cells that are not “activated” and recognized as HIV-infected by other cells in the immune system). This, the researchers write, may have contributed to the gradual reduction of the viral reservoir in some post-treatment controllers; a reservoir made up mostly of cells with short life spans can be expected to shrink as those cells die off.

Finally, based on observations of patients in the French Hospital Database on HIV study and in other studies, the authors estimate that PTCs may represent 5% to 15% of patients who started HIV therapy during primary infection and later interrupted treatment. This percentage is much higher than the estimated percentage of elite controllers (less than 1%). Among PTCs in the French Hospital Database on HIV study, the researchers estimate, the probability of maintaining viral control (defined as a viral load below 400 copies/mL) for 24 months was 15.3%.

What Do These Findings Mean Going Forward?

The study’s key implication is that starting HIV treatment during primary infection and keeping it up for a certain length of time may allow for viral control without a lifetime of antiretroviral therapy—the definition of a functional cure.

That’s a thrilling prospect, of course, but there are a few catches. While the VISCONTI findings are enlightening and add to a growing body of evidence for the benefits of early treatment, the study involves only 14 people in a single country. In addition, although they were able to detect important differences between PTCs and elite controllers, who spontaneously suppress HIV, the study authors acknowledge that they “cannot rule out the possibility that spontaneous control may have been masked in some cases by early therapy initiation.”

Another limitation is that most people who are in the primary phase of HIV infection don’t know it. Standard HIV tests look for antibodies produced against HIV, not for HIV itself, and since the immune system may not produce these antibodies for weeks to months, HIV may be present and replicating like mad before an antibody test turns up positive. A different testing technology, called PCR testing, detects HIV’s own genetic material and therefore allows for much earlier diagnosis. Unfortunately, this test’s higher cost and more frequent false-positive results limit its use for routine testing.

But although obstacles and questions remain, this and other recent discoveries regarding early HIV treatment, reduced viral reservoirs, and viral control in the absence of antiretroviral therapy—along with renewed interest in cure research, following the experience of “Berlin Patient” Timothy Brown—make this a very exciting time in the search for an HIV cure.

Reilly O’Neal is the editor of BETA.

Selected Sources

Bacchus, C. and others. Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption. XIX International AIDS Conference. Washington, DC. July 22-27, 2013. Abstract # THAA0103.

Sáez-Cirión, A. and others. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathogens 9(3): e1003211. March 2013.

 

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