Lifelong Antiretroviral Therapy Unsustainable, Experts Say

One-Time HIV Treatments Must Replace ART

Robert Lowes

May 31, 2011 — Although more HIV-infected individuals are receiving life-saving antiretroviral therapy (ART) at 30 years after AIDS was identified, researchers must also find cures and vaccines to eliminate the need for this lifelong and challenging treatment, according to an article published online May 31 in the Annals of Internal Medicine by 2 leaders of the National Institute of Allergy and Infectious Diseases (NIAID).

Carl Dieffenbach, PhD, director of the NIAID Division of AIDS, and NIAID director Anthony Fauci, MD, write that lifelong, daily-dosage ART is not a sustainable strategy in a world where 2.5 million people become infected with HIV each year.

To help them stick to their drug regimen, patients receiving ART require a healthcare system capable of delivering long-term care similar to the model used in the United States to manage patients with diabetes.

In an obvious nod to developing nations ravaged by HIV, the authors write that the need for long-term care creates a formidable challenge for "resource-limited settings and for patients who lack adequate health care coverage." They note that ART is given to only 1 in 3 HIV-infected individuals in the world who need it.

Cure Possibilities

One solution, write Drs. Dieffenbach and Fauci, is devising a 1-time cure for HIV, which could fall into 2 different categories. Researchers could find a true "sterilizing" cure that completely eradicates the virus from the body or a "functional" cure that permanently suppresses the virus to a harmless level.

In the case of a sterilizing cure, researchers must solve the problem of cells remaining latently infected even though ART has reduced blood levels of HIV to near zero. When ART ends, these latently infected cells cause the infection to recur.

Investigators are experimenting with ways to flush out the virus from "this persistent reservoir" so it can be treated with ART. Key to the success of this strategy is the development of a simpler, more accurate way of measuring the latent HIV reservoir.

Despite its treatment limitations, ART nevertheless promises to play an important role in preventing HIV infection through preexposure prophylaxis (PrEP) and treatment-as-prevention, according to Drs. Dieffenbach and Fauci. They point to the CAPRISA 004 trial, in which a vaginal gel containing tenofovir lowered the risk for HIV infection in sexually active women by 39%.

Likewise, the iPrEx study showed that a daily regimen of emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg (Truvada, Gilead Sciences), was 44% effective in preventing infection in men who have sex with men and in transgendered women. The risk for infection decreased by 73% in those who took their pills on 90% or more of the days in the study.

Cautious Optimism

An example of treatment-as-prevention, not discussed in the article, is a recent trial showing that ART given to a group of HIV-infected individuals — most of whom were heterosexual — with relatively healthy immune systems was 96% effective in preventing infection in their partners.

The "ideal cornerstone" of a prevention strategy, the authors write, would be a safe and effective vaccine. The quest for such a vaccine has met with repeated failures, although several recent advances have led to "a degree of cautious optimism." For example, researchers have found that sexual transmission of HIV often appears to begin with a single "founder virus" that differs from the various strains that develop over time in an infected person.

This insight may create new targets for vaccines. In addition, a 2009 vaccine trial in Thailand reported 31% efficacy in preventing HIV infection — a modest success that future trials can build on.

A vaccine that guards against all forms of sexual transmission — including blood-borne transmission — would work in tandem with a growing number of other evidence-based prevention strategies ranging from PrEP to adult male circumcision, according to Drs. Dieffenbach and Fauci.

"Researchers are unlikely to achieve transformative successes in HIV with a unidimensional approach," they write. "Instead, this will require various versions of combination prevention strategies, depending on the target population."

The authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online May 31, 2011.