Low-cost drugs package saves lives of people starting Tx late

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Treating people who start HIV treatment late with a package of low-cost drugs to prevent serious infections saves three lives for every 100 people treated, according to the findings of a trial led by the Medical Research Council (MRC) Clinical Trials Unit at the University College London (UCL).

The results were from the REALITY trial, which involved 1,805 adults, teenagers and children from Kenya, Malawi, Uganda and Zimbabwe and was funded by the MRC, the UK’s department for international development (DFID) and Wellcome.

Current practice in Africa is to start HIV treatment together with one antibiotic, cotrimoxazole, to prevent a range of infections. But when people start treatment late, HIV has already caused severe damage to the immune system and patients have very low numbers of an important blood cell (called CD4 cells) that fights infections. All of patients in the REALITY trial had under 100 CD4 cells per cubic millimetre of blood when the range in healthy people is between 500 and 1500.

The researchers recommend that people in Africa starting HIV treatment with low CD4 counts should be given the enhanced prevention package for the first 12 weeks of HIV treatment.

Around one in five people starting HIV medicines in low-income countries have CD4 counts under 100 when they start treatment. People living with HIV with low CD4 counts are at high risk of developing serious illnesses after starting HIV treatment and around one in ten will die within the first few weeks of starting treatment because their immune systems cannot recover fast enough.

The REALITY trial looked at ways to reduce these deaths in the early stages of treatment. One of the strategies it tested was to prevent infections caused by bacteria and fungi by using an extra package of drugs including a TB drug (isoniazid), an antifungal (fluconazole), an antibiotic (azithromycin), and an anti-worm drug (albendazole), in addition to routine cotrimoxazole.

The prevention package of anti-infection drugs reduced deaths and HIV-related illnesses. Six months after starting HIV treatment, nine out of every 100 patients taking the extra anti-infection drugs had died, compared with 12 out of every 100 patients taking just cotrimoxazole and HIV treatment. Thus the package saved at least three lives for every 100 people taking it, a relative reduction of 25%.

“Because many people with HIV in Africa do not start anti-HIV drugs until their immune system has been badly damaged by the disease, they are at a high risk of dying within the first few weeks of treatment,” explained Professor Di Gibb (MRC Clinical Trials Unit, UCL). “We found that not only did this additional drugs package prevent early deaths among people starting HIV treatment with low CD4 counts, but that it also reduced the numbers of severe Aids illnesses and hospital admissions.”

Professor James Hakim from the University of Zimbabwe, said: “Another important result we saw was that although the average CD4 count among the 1,805 people starting treatment in REALITY was only 36 cells per cubic millimetre, which is very low, half of them had either no symptoms or only very minor ones. This shows the importance of measuring CD4 counts before starting HIV treatment, as there is no other way to identify many who would benefit from this package.”

The drugs used in the enhanced drugs package are all relatively low cost. The total cost ranged from £5 in Kenya to £26 in Zimbabwe. Taking the minimum drug costs across the countries involved in the trial, the drugs package was about £4 more expensive than the standard cotrimoxazole drug costs (£4.34 vs £0.59).

Health economists conducted an analysis which showed that the package was highly cost-effective in all of the countries involved in the trial.

Background: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%.
Methods: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of 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, as compared with standard prophylaxis (trimethoprim–sulfamethoxazole alone). The primary end point was 24-week mortality.
Results: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.
Conclusions: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects.

James Hakim, Victor Musiime, Alex J Szubert, Jane Mallewa, Abraham Siika, Clara Agutu, Simon Walker, Sarah L Pett, Mutsa Bwakura-Dangarembizi, Abbas Lugemwa, Symon Kaunda, Mercy Karoney, Godfrey Musoro, Sheila Kabahenda, Kusum Nathoo, Kathryn Maitland, Anna Griffiths, Margaret J Thomason, Cissy Kityo, Peter Mugyenyi, Andrew J Prendergast, A Sarah Walker, Diana M Gibb

University College London material
New England Journal of Medicine abstract

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