Add antimicrobials to cut death risk in advanced HIV

Trial shows survival benefit without affecting HIV suppression

While anti-HIV treatment is becoming much more widely available in developing countries, many people still present for care with a severely damaged immune system and about 10% die from infection in the weeks after beginning HIV treatment, according to A. Sarah Walker, PhD, of University College London, and colleagues.

But in a randomized trial, those getting an enhanced package of antimicrobial drugs had a 27% lower risk of death than those getting standard prophylaxis with trimethoprim-sulfamethoxazole, Walker and colleagues reported in the July 20 issue of the New England Journal of Medicine.

The benefit was sustained for at least 48 weeks and came without affecting HIV suppression or increasing toxicity, the investigators found.

The enhanced prophylaxis could be especially important in places where lab tests such as cryptococcal antigen testing, tuberculosis diagnostics, and bacterial culture are not available, commented Nathan Ford, PhD, and Meg Doherty, MD, PhD, both of the World Health Organization's Department of HIV/AIDS in Geneva.

"This approach is practical for reducing illness and death from the most common causes, which can occur rapidly," Ford and Doherty argued in an accompanying editorial in the journal.

But they cautioned that there are "some concerns with this approach that merit careful assessment," including the risk of creating resistance to some of the drugs involved and the cost-effectiveness of using blanket prophylaxis where appropriate diagnostic tests are available.

The so-called REALITY trial -- for Reduction of Early Mortality in HIV Infected Adults and Children Starting Antiretroviral Therapy -- enrolled 1,895 people in Uganda, Zimbabwe, Malawi, and Kenya.

All had advanced HIV, evidenced by a count of CD4-positive T cells that was less than 100 per mm³ (the median was 37), although nearly half were either without symptoms or were only mildly symptomatic.

In a factorial, open-label fashion, the researchers investigated three interventions -- enhanced antimicrobial prophylaxis, adding the drug raltegravir to the anti-HIV therapy, and supplying supplemental food -- but they are so far only reporting the effects of the prophylaxis package.

The primary outcome of the analysis was all-cause mortality 24 weeks after the initiation of HIV treatment but the researchers followed patients out to 48 weeks.

Some 899 patients were assigned to the standard trimethoprim-sulfamethoxazole prophylaxis, while 906 got the enhanced package, with continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole.

At 24 weeks, Walker and colleagues reported, 108 patients on standard prophylaxis had died, compared with 80 getting the enhanced package, yielding a hazard ratio of 0.73 favoring the latter (P=0.03).

And the effect was sustained: at 48 weeks 127 and 98 patients in standard and enhanced prophylaxis, respectively, had died, for a hazard ratio of 0.76, which remained significant, they found.

As well, they reported, enhanced prophylaxis significantly lowered the incidence of new:

• Tuberculosis (7.1% versus 10.2%)
• Cryptococcal infections (1.0% versus 2.6%)
• Candidiasis (1.1% vs. 2.6%)
• Hospital admissions (17.0% vs. 20.7%)

Deaths from cryptococcus and from unknown causes were significantly lower among those getting the enhanced package, but there was no significant between-group difference in the rate of severe bacterial infection, Walker and colleagues reported.

Rates of serious adverse events and grade 4 adverse events were lower but not significantly so in the enhanced-prophylaxis group, while rates of HIV viral suppression and adherence to antiretroviral therapy were similar in the two groups, they reported.

The enhanced prophylaxis is "relatively inexpensive, has a low pill burden and an acceptable side-effect profile, and would be easy to implement" in low-income settings, they concluded, because it relies only on clinical screening CD4 testing to find asymptomatic patients with advanced HIV.

The report comes as researchers and clinicians are preparing to meet next week in Paris for the 9th International AIDS Society meeting on HIV science next week.