Tx package reduced mortality risk in advanced HIV patients – REALITY study

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A package of enhanced prophylaxis against infections significantly reduced the risk of death in adults and children with advanced HIV after starting antiretroviral treatment in the REALITY study carried out in Kenya, Malawi, Uganda and Zimbabwe.

Professor James Hakim of the University of Zimbabwe was presenting the results at the 21st International AIDS Conference in Durban, South Africa, last month.

REALITY was a large clinical trial designed to evaluate strategies for reducing the risk of death in people who start antiretroviral treatment 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 six months after starting treatment remains high for adults and children.

Hakim said that death rates in the first six months of treatment can be six to ten times higher in low and middle-income countries than in the developed world in people who start treatment with very advanced HIV disease, due to infections such as tuberculosis (TB) and Cryptococcus, and due to severe malnourishment.

Identifying ways of reducing the risk of death in people who start antiretroviral therapy 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 deaths in the first months after starting ART can bring down death rates. Although cotrimoxazole prophylaxis is widely implemented, isoniazid preventive treatment still fails to be provided despite a World Health Organisation recommendation for its use in people living with HIV.

The REALITY trial, carried out in Kenya, Malawi, Uganda and Zimbabwe evaluated three strategies for reducing the risk of death: prophylaxis against the infections most commonly associated with death in advanced HIV disease (tuberculosis, cryptoccus, bacterial infections and protozoal infections), compared to cotrimoxazole prophylaxis alone; intensification of antiretroviral therapy with an integrase inhibitor in order to reduce viral load more quickly, leading to more rapid immune reconstitution, compared to three-drug ART alone; and supplementary ready-to-use food for 12 weeks (two 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 antiretroviral therapy according to national guidelines (predominantly tenofovir/emtricitabine and efavirenz). In addition, participants underwent three randomisations (factorial randomisation), to each of the study interventions or to a control arm. Participants were therefore randomised to one intervention and then each group was randomised to receive a further intervention or control, and so on.

Participants randomised to receive enhanced prophylaxis received: 12 weeks of isoniazid (INH 300mg) & 25mg vitamin B6 per day for TB prevention; 12 weeks of fluconazole 100mg per day for prevention of Cryptococcus and other fungal infections; 5 days of azithromycin 500mg per day as an anti-bacterial and anti-protozoan; and a single dose of albendazole (400mg) as an anti-helminth (worming) treatment.

Participants in both arms received daily cotrimoxazole prophylaxis.

Researchers said 1,805 patients were randomised, 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 of participants was 37 cells/mm3 and approximately 36% had CD4 cell 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 disease at baseline (symptomatic). Four per cent of participants were children or adolescents aged 5 to 17 years.

The primary study outcome was the death rate 24 weeks after starting treatment. Intent to treat analysis which counted everyone randomised 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 tuberculosis or bacterial infections. The investigators concluded that, in most cases, the causes of death were multi-factorial. 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. Hospitalisation for any cause was also significantly reduced in the enhanced prophylaxis arm. There was no excess of serious adverse definitely or possibly related to prophylaxis, nor of adverse events leading to modification of OI prophylaxis.

The patient population in the raltegravir randomisation (902 RAL, 903 SOC) had very similar characteristics to those assigned to the enhanced prophylaxis randomisation. Participants randomised to the raltegravir arm received raltegravir for 12 weeks in addition to three-drug antiretroviral therapy.

As in the enhanced prophylaxis arm, the primary study outcome was the death rate 24 weeks after starting treatment. Intent to treat analysis which counted everyone randomised showed no significant difference between the raltegravir arm and the standard of care 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 the receipt of enhanced prophylaxis alone.

Results of the nutrition randomisation 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 $7.16 for 12 weeks of prophylaxis in Kenya to $32-99 in Zimbabwe, with big variations in the costs of fluconazole (around five times more expensive in Malawi than in other countries) and azithromycin (around five times more expensive in Zimbabwe than in other countries). There was a similarly large variation in the drug-cost per life year saved, ranging from $268 per life-year saved in Kenya to $1,211 in Malawi and $1,237 in Zimbabwe. An essential question 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.

Abstract 1
Background: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV-infected adults and children with advanced disease in sub-Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown.
Methods: The REALITY 2x2x2 factorial open-label trial (ISRCTN43622374) randomised ART-naïve HIV-infected adults and children >5 years with CD4< 100 cells/mm3. This randomisation compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti-tuberculosis) and fluconazole (anti-cryptococcal/candida), 5 days azithromycin (anti-bacterial/protozoal) and single-dose albendazole (anti-helminth)), versus standard-of-care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed-dose-combination. Two other randomisations investigated 12-week adjunctive raltegravir or supplementary food. The primary endpoint was 24-week mortality. Results: 1805 eligible adults (n=1733;96.0%) and children/adolescents (n=72;4.0%) (median 36 years; 53.2% male) were randomised to enhanced (n=906) or standard prophylaxis (n=899) and followed for 48 weeks (3.8% loss-to-follow-up). Median baseline CD4 was 36 cells/mm3 (IQR 16-62) but 47.3% were WHO stage 1/2. 80(8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio[aHR]=0.73 (95% CI 0.54-0.97) p=0.03; Figure) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR=0.75 (0.58-0.98) p=0.04), with no evidence of interaction with the two other randomisations (p>0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p=0.02), cryptococcal disease (p=0.01), oral/oesophageal candidiasis (p=0.02), deaths of unknown cause (p=0.02), and (marginally) hospitalisations (p=0.06) but not presumed severe bacterial infections (p=0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p=0.06). CD4 increases and VL suppression were similar between groups (p>0.2).
Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV-infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy-makers should consider adopting and implementing this low-cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated.

Authors
J Hakim, V Musiime, AJ Szubert, A Siika, J Mallewa, C Agutu, SL Pett, M Bwakura-Dangarembizi, A Lugemwa, S Kaunda, M Karoney, K Maitland, A Griffiths, C Kityo, P Mugyenyi, AJ Prendergast, AS Walker, DM Gibb, REALITY Trial Team

Abstract 2
Background: Early mortality after initiating antiretroviral therapy (ART) is high among HIV-infected adults and children with advanced disease in Sub-Saharan Africa. Intensifying ART with an integrase inhibitor should reduce viral load (VL) faster, but whether this reduces early mortality is unknown.
Methods: The REALITY 2x2x2 factorial open-label trial (ISRCTN43622374) randomised ART-naïve HIV-infected adults and children >5 years with CD4< 100 cells/mm3 from Kenya, Malawi, Uganda and Zimbabwe. This randomisation compared initiating ART with 2NRTI+NNRTI with or without 12-week raltegravir intensification. Two other randomisations investigated 12-week enhanced infection prophylaxis or supplementary food. The primary endpoint was 24-week mortality.
Results: 1805 eligible adults (n=1733;96.0%) and children/adolescents (n=72;4.0%) (median 36 years; 53.2% male) were randomised to raltegravir-intensified (n=903) or standard (n=902) ART and followed for 48 weeks (3.8% loss-to-follow-up). Median baseline CD4 was 36 cells/mm3 (IQR 16-62) and VL 230,000 c/ml (72.5%≥100,000 c/ml). At 4, 12, 24 and 48 weeks, VL was < 50 c/ml in 42.8%, 74.1%, 77.2% and 82.9% in 12-week raltegravir-intensified versus 14.5%, 54.6%, 76.0% and 79.5% standard ART (p< 0.001, < 0.001, 0.59, 0.12, respectively) (Figure). CD4 increases through 24 weeks were similar (p=0.82), although a small difference became apparent at 48 weeks (+163 cells/mm3 intensified versus +148 cells/mm3 standard, p=0.04). 97(10.9%) intensified versus 91(10.2%) standard ART died before 24 weeks (adjusted hazard-ratio[aHR]=1.09 (95% CI 0.82-1.46) p=0.54); 110(12.4%) versus 115(13.0%) respectively died before 48 weeks (aHR=0.98 (0.75-1.27) p=0.86), with no evidence of interaction with the two other randomisations (p>0.7). There was no difference in time to first WHO 3/4 event or death (p=0.31). Serious adverse events (AEs), grade 3/4 AEs and drug-related AEs (adjudicated blind to randomisation) were similar in both groups (p>0.3).
Conclusions: 12-week raltegravir-intensified ART was well tolerated, resulted in faster VL reduction through 24 weeks and increased CD4 at 48 weeks, but did not reduce mortality or WHO 3/4 events.

Authors
C Kityo, A Siika, AJ Szubert, J Mallewa, M Bwakura-Dangarembizi, S Kabahenda, S Mwaringa, SL Pett, A Griffiths, A Lugemwa, S Wachira, G Musoro, C Rajapakse, T Etyang, J Abach, P Wavamunno, L Nyondo-Mipando, A Reid, K Nathoo, J Hakim, DM Gibb, AS Walker, REALITY trial team

Aidsmap material
AIDS2016 abstract 1
AIDS2016 abstract 2


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