Early Antiretroviral Therapy Cuts HIV-Related Mortality by 75%

From MedscapeCME Clinical Briefs

News Author: Martha Kerr
CME Author: Désirée Lie, MD, MSEd

July 27, 2010 — Researchers in Haiti are reporting that early initiation of antiretroviral therapy in HIV-infected adults, beginning when CD4+ T-cell counts drop below 350 cells/mm3, is associated with a 4-fold lower rate of death and a 2-fold lower rate of incident tuberculosis, compared with the old standard of waiting to initiate treatment until CD4+ counts fall below 200 cells/mm3.

These findings are in line with the newly updated World Health Organization (WHO) guidelines, issued November 30, 2009, which recommend early initiation of antiretroviral therapy.

The findings were presented at AIDS 2010, the XVIII International AIDS Conference, and have been published in the July 15 issue of the New England Journal of Medicine.

The study involved 816 HIV-infected adults in Haiti with a confirmed CD4+ T-cell count that was between 200 and 350 cells/mm3 at baseline and no history of an AIDS illness.

Patients were randomized to early treatment (within 2 weeks of enrollment) with zidovudine, lamivudine, and efavirenz, or to standard treatment with the same regimen initiated when CD4+ T-cell counts fell below 200 cells/mm3 or when clinical AIDS developed. Median time to treatment in the standard-care group was 2 years. All subjects also received isoniazid and trimethoprim–sulfamethoxazole prophylaxis with nutritional support.

Patrice Severe, MD, from Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), in Port au Prince, and colleagues assessed patients monthly for a median of 21 months from 2005 to 2008. The primary study endpoint was survival.

There were 23 deaths in the standard-care group and 6 in the early-treatment group (hazard ratio [HR] for standard care, 4.0; 95% confidence interval [CI], 1.6 - 9.8; P = .001). There were 36 incident cases of tuberculosis in the standard-care group, and 18 in the early-treatment group (HR, 2.0; 95% CI, 1.2 - 3.6; P = .01).

Dr. Severe and colleagues write that "antiretroviral therapy that is initiated when the CD4+ T-cell count is greater than 200 and less than 350 per cubic millimeter, as compared with antiretroviral therapy that is deferred until the CD4+ T-cell count falls to 200 per cubic millimeter or less or an AIDS-defining illness develops, results in a 75% reduction in the rate of death and a 50% decrease in the incidence of tuberculosis."

Patients receiving standard care had higher rates of infectious diseases in general and more treatment-limiting drug reactions than those in the early-treatment group. They also required more frequent monitoring of CD4+ T-cell counts. With standard care, the survival rate is approximately 80% at 5 years.

Delaying treatment until CD4+ cell counts fall below 200 cells/mm3 "consumed resources and the time of highly trained healthcare workers, factors that may in part offset the cost of starting antiretroviral therapy earlier," Dr. Severe and colleagues observe.

"At current pricing, 2 years of antiretroviral drugs will cost approximately $400 per person. Thus, for a cost of approximately $400 per person, the rate of death can be decreased by 75%, and the incidence of active tuberculosis by 50%," the researchers write.

Meanwhile, Médecins Sans Frontières (MSF) held a press conference on July 15 to announce cuts in AIDS funding from donor countries to resource-poor countries, and to release a new report on the consequences of delayed, deferred, or denied AIDS treatment.

The report was presented by Nathan Ford, medical coordinator of the MSF Campaign for Access to Essential Medicines. Among the consequences itemized in the report are the following:

* Limiting treatment means "choosing who lives and who dies"
* Delaying or deferring treatment leads to increases in transmission, illness, and death
* Losing a stable drug supply means sharp increases in viral load and a resulting increase in HIV transmission
* Switching from first-line drugs to those with a lower base price means using less effective and more toxic drugs, and an increase in comorbidities
* Cutting back on funding for treatment means sacrificing long-term survival

Implementing the new WHO recommendations "means lowering the treatment threshold and increasing the number of patients eligible for treatment by about 30% to 40%," Mr. Ford told Medscape Medical News.

Mr. Ford charged donor countries with being "short-sighted" by backing the old WHO recommendations of initiating antiretroviral treatment when CD4+ counts fall below 200 cells/mm3.

"Early treatment should be seen as less expensive, with increased survival, less toxicity, and fewer comorbidities," he told Medscape Medical News. "This point has been missed in some of their policies. . . . HIV is a life-long illness. No treatment doesn't mean [patients] go away. It just means they come back later and sicker," and put a costly strain on limited resources that outstrip the small savings seen with a policy of delaying treatment."

Sharonann Lynch, MSF HIV/AIDS policy advisor, who moderated the conference, asserted that donor countries should not be allowed to back "Big Pharma," and pharmaceutical companies should be made to see that the policy of delayed treatment is not to their advantage, either.

The GHESKIO study was supported in part by grants from the National Institute of Allergy and Infectious Diseases and from the Fogarty International Center. Support for antiretroviral medications was provided by the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and by GlaxoSmithKline and Abbott. The researchers have disclosed no relevant financial relationships. Mr. Ford and Ms. Lynch are employees of Médecins Sans Frontières and have disclosed no relevant financial relationships.

N Engl J Med. 2010;363:257-265.
Clinical Context

Early antiretroviral treatment in HIV-infected patients without AIDS but with CD4+ counts between 200 and 350 cells/mm3 has been found in observational studies to be associated with better survival duration and lower rates of tuberculosis infection.

This is an open-label randomized trial to compare mortality associated with early vs standard initiation of antiretroviral therapy in adults infected with HIV-1 with CD4+ counts between 200 and 350 cells/mm3.