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AIDS 2016: Infection Prophylaxis Reduces Risk of Death for People Starting HIV Treatment Late


A package of enhanced prophylaxis against infections significantly reduced the risk of death for adults and children with advanced HIV disease after starting antiretroviral treatment in a randomized study, James Hakim from the University of Zimbabwe reported at the 21st International AIDS Conference (AIDS 2016) last month in Durban. Another analysis showed that intensifying treatment by adding raltegravir did not offer added benefits. 

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Hakim presented the results of the REALITY study, a large clinical trial designed to evaluate strategies for reducing the risk of death among people who start antiretroviral therapy (ART) with very low CD4 cell counts (below 100 cells/mm3). Late presentation with HIV disease, often with symptomatic disease, remains common in sub-Saharan Africa. The risk of death in the first 6 months after starting treatment remains high for adults and children.

Hakim told an AIDS 2016 press conference that death rates during the first 6 months of treatment can be 6 to 10 times higher in low- and middle-income countries than in the developed world among people who start treatment with very advanced HIV disease, due to infections such as tuberculosis (TB) and Cryptococcus, as well as severe malnourishment.

Identifying ways of reducing the risk of death among people who start ART with very low CD4 counts is essential if the number of AIDS-related deaths is to be reduced. In particular, more evidence is needed to show whether a package of aggressive prophylaxis against the infections that most frequently cause death during the first months after starting ART can bring down mortality rates. Although cotrimoxazole prophylaxis is widely implemented, isoniazid preventive treatment for TB still is often not provided, despite a World Health Organization (WHO) recommendation for its use in people living with HIV.

The REALITY trial, carried out in Kenya, Malawi, Uganda, and Zimbabwe, evaluated 3 strategies for reducing the risk of death.

  • Prophylaxis against the infections most commonly associated with death in advanced HIV disease (TB, Cryptococcus, bacterial infections, and protozoal infections), compared to cotrimoxazole prophylaxis alone.
  • Intensification of ART with an integrase inhibitor in order to reduce viral load more quickly, leading to more rapid immune reconstitution, compared to 3-drug ART alone.
  • Supplementary ready-to-use food for 12 weeks (2 packets of a high-energy, low-protein food per day) to improve nutrition, compared to targeted nutritional support for those with poor nutritional status according to local protocols.

All participants in the study received ART according to national guidelines (predominantly tenofovir/emtricitabine and efavirenz). In addition, participants underwent 3 randomizations (factorial randomization) to each of the study interventions or to a control arm. Participants were therefore randomized to one intervention and then each group was randomized to receive a further intervention or control, and so on.

Prophylaxis Randomization

Participants randomized to receive enhanced infection prophylaxis received:

  • 12 weeks of 300 mg isoniazid and 25 mg vitamin B6 per day for TB prevention;
  • 12 weeks of fluconazole 100 mg per day for prevention of Cryptococcus and other fungal infections;
  • 5 days of azithromycin 500 mg per day as an anti-bacterial and anti-protozoal;
  • A single 400 mg dose of albendazole as an anti-helminth (worming) treatment.

Participants in both study arms received daily cotrimoxazole prophylaxis.

A total of 1805 people were randomized, 906 to the enhanced prophylaxis arm and 899 to the standard of care arm. The study population had very advanced HIV disease. The median CD4 cell count was 37 cells/mm3 and approximately 36% had CD4 counts below 25 cells/mm3. Almost three-quarters had a viral load above 100,000 copies/mL and just over half had WHO stage 3 or 4 HIV disease (symptomatic) at baseline. 4% of participants were children or adolescents aged 5 to 17 years.

The primary study outcome was the death rate at 24 weeks after starting treatment. Intent-to-treat analysis, which counted everyone randomized, showed that enhanced prophylaxis was associated with a significantly reduced risk of death. 8.9% of those in the enhanced prophylaxis arm died compared to 12.2% of those in the standard of care arm, a risk reduction of 27% (HR 0.73; 95% CI 0.54-0.97; p=0.03), and this difference was sustained at week 48 (HR 0.75; 95% CI 0.58-0.98; p=0.04).

Analysis of the primary causes of death showed that death due to Cryptococcus was significantly reduced in the enhanced prophylaxis arm (p=0.03), but there was no difference in rates of death due to TB or bacterial infections. The investigators concluded that, in most cases, the causes of death were multifactorial.

Nevertheless, the study found that enhanced prophylaxis was associated with a reduction in new cases of TB, cryptococcal disease, or candida, but not of bacterial infections. Hospitalization for any cause was also significantly reduced in the enhanced prophylaxis arm. There was no excess of serious adverse events definitely or possibly related to prophylaxis, nor of adverse events leading to modification of opportunistic infection prophylaxis.

Antiretroviral Intensification Randomization


The patient population in the ART intensification randomization (902 raltegravir; 903 standard-of-care) had very similar characteristics to those in the enhanced prophylaxis randomization.

Participants were randomized to receive raltegravir (Isentress) for 12 weeks in addition to 3-drug ART, which the control group received a standard ART regimen. As in the enhanced prophylaxis arm, the primary study outcome was the death rate at 24 weeks after starting treatment.

Cissy Kityo from the Joint Clinical Research Centre in Kampala reported that intent-to-treat analysis showed no significant difference between the raltegravir arm and the standard-of-care arm in mortality at 24 weeks, nor in any secondary outcomes with the exception of grade 4 adverse events definitely or probably related to the study regimen (p=0.03).

Receipt of raltegravir was not found to interact with receipt of the enhanced prophylaxis intervention; in other words, the addition of raltegravir to enhanced prophylaxis did not result in a superior outcome when compared to enhanced prophylaxis alone.

Results of the nutrition randomization were not presented.


The investigators concluded that policy-makers should consider adopting and implementing the enhanced prophylaxis package, which they estimate could save 3.3 lives for every 100 people treated with the package.

A preliminary analysis of the cost of the enhanced prophylaxis package found that costs varied from US$7.16 for 12 weeks of prophylaxis in Kenya to $32.99 in Zimbabwe, with big variations in the costs of fluconazole (around 5 times more expensive in Malawi than in other countries) and azithromycin (around 5 times more expensive in Zimbabwe than in other countries). There was a similarly large variation in drug cost per life-year saved, ranging from $268 in Kenya to $1211 in Malawi and $1237 in Zimbabwe.

An essential issue for policy-makers seeking to implement this package of care will be to ensure the lowest possible costs for the drugs used, and to identify local regulatory and supply chain barriers to cost reduction.



J Hakim, V Musiime, AJ Szubert, et al. Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial. 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract FRAB0101LB.

C Kityo, A Siika, AJ Szubert, et al. 12-week raltegravir-intensified quadruple therapy versus triple first-line ART reduces viral load more rapidly but does not reduce mortality in severely immunosuppressed African HIV-infected adults and older children: the REALITY trial. 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract FRAB0102LB.