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IDCM Issue 12: TB, Cryptococcus, and Antiretrovirals: Key Studies from 2017 CROI for All Providers
Natasha Chida, MD, MSPH
There was no shortage of promising developments presented last month at the 24th Conference on Retroviruses and Opportunistic Infections (CROI). This annual conference gathers together researchers from around the world working on the cutting edge of basic, translational, and clinical HIV and opportunistic infections. This edition of ID Clinical Minute reviews a few of many key studies presented at CROI that are of relevance to all providers who see patients with HIV, either in primary care or in consultation.
Promise for Single Daily L-AmB in Cryptococcal Meningitis Treatment
Promising trial results were presented that evaluated a single high-dose of liposomal amphotericin B (L-Amb) as a treatment option for cryptococcal neoformans meningitis (CM). CM continues to be a significant source of morbidity and mortality among people living with HIV (PLWH). An estimated 1 million cases occur among PLWH annually; of those, 625,000 die.1 The majority of cases occur in sub-Saharan Africa, where cryptococcus is the most common cause of meningitis. Unfortunately, the first-line treatment of CM includes at least 2 weeks of liposomal amphotericin B (L-AmB), an IV drug that may cause significant side effects (such as renal failure).2
In this non-inferiority study of 80 persons with HIV-associated CM in Botswana and Tanzania, participants were randomized to receive one of 4 treatment regimens:
1. 2 weeks of L-AmB at 3mg.kg.day, plus 1200 mg of fluconazole daily (the control)
2. 1 dose of L-AmB at 10 mg/kg, plus 1200 mg of fluconazole daily
3. 2 doses of L-AmB at 5 mg/kg/day, plus 1200 mg of fluconazole daily; or
4. 1 dose of L-AmB 10 at 10 mg/kg/day, followed by 5 mg/kg/day on days 3 and 7.3
The primary endpoint was fungicidal activity as obtained through serial CSF cultures. The median age was 38 years, while the median CD4 count was 34 cells/mm3. Fifty-four percent of the sample was male and 33% were on antiretroviral (ARV) therapy. The rate of fungal clearance in all three short-course high-dose arms was non-inferior to the control arm, even after adjusting for baseline fungal burden, mental status, and CD4 count. There was also no difference in the primary endpoint among the three intervention groups. In terms of mortality, overall 29% of the sample died; this included 29% of the control arm, 22% of the single dose arm, 15% of the 2-dose arm, and 48% of the 3-dose arm. Based on this study, a single 10 mg/kg /daily dose of L-Amb seems to be a promising treatment option, and is being studied in a phase 3 trial.
Preemptive Prednisone Therapy Appears to Reduce TB-IRIS in High Risk Patients
Immune reconstitution syndrome is a condition that occurs when the immune system is restored and creates an immune response to a pathogen present within the body. This is a well-described phenomenon that occurs in 8-40% of patients co-infected with HIV and TB who begin ARV therapy after TB is diagnosed.4 IRIS can cause mild symptoms to life-threatening disease. The risk of developing IRIS is higher with lower CD4 counts; however, early ARV therapy in patients co-infected with HIV and TB and CD4 counts <50 cells/mm3 improves mortality. As such, some guidelines recommend that co-infected patients who are not on ARVs and who have a CD4 count of <50 cells/mm3 initiate ARVs within 2 weeks of starting TB treatment, while patients who have CD4 counts > than 50 cells/mm3 are recommended to begin ARV therapy after 8-12 weeks of TB treatment.4 A question has been whether administering preemptive corticosteroids (a therapeutic option for IRIS) with ARV initiation in co-infected patients is helpful.
In this double-blind randomized controlled trial, 240 ART-naïve patients co-infected with HIV and TB who had CD4 counts ≤ 100 cells/mm3 were randomized to receive, within 30 days of initiating TB treatment, either a) ARVs and a placebo, or b) ARVs with 2 weeks of 40 mg of prednisone daily X 2 weeks, followed by 2 weeks of 20 mg daily.5 Participants were followed for 12 weeks. The primary endpoint was the development of TB-IRIS. Men represented 60% of the sample, while the median age was 36.8 years. The median CD4 count was 49 cells/mm3, while the median HIV RNA was 337,777; a microbiologic diagnosis of TB was made in 175 participants. A significant difference in IRIS incidence was noted, with 56 cases occurring in the placebo arm (46.7%) and 30 in the prednisone arm (32.5%; RR of 0.7, p=0.02). There was thus a 30% risk reduction with prednisone. There was no difference in death between the arms (4 in the placebo arm and 5 in the prednisone arm p=0.17]), or in severe infections (18 in the placebo arm and 11 in the prednisone arm [p=0.1]).
Darunavir May Have an Effect on Cardiovascular (CVD) Risk
It is known that older protease inhibitors such as indivanir and lopinavir are associated with increased CVD risk.6 However, the risk is not known for modern protease inhibitors, such as darunavir (DRV) and atazanavir (ATZ). The Data Collection on Adverse Events of Anti-HIV Drugs is a multi-cohort prospective study that evaluates adverse events from ARV therapy. This sub-study evaluated cardiovascular risk in patients receiving either darunavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATZ/r).7
35,711 patients were followed from January 2009 until (a) their first evidence of CVD, (b) their last visit + 6 months, or (c) February 2016. CVD was defined as a myocardial infarction, stroke, sudden cardiac death, or need for a coronary bypass, a coronary angioplasty, or carotid endarterectomy. Approximately 74% of the sample was male; the median age was 44 years. Approximately 48% were white. Of the sample, 1157 persons developed CVD during a median 7 years of follow-up. In comparing the crude CVD risk of persons who did and didn’t receive ATZ/r, a small increased crude risk of CVD was noted (6.68/1000 person years vs. 5.03/1000 person years, respectively). In comparing persons who did and did not receive DRV/r, a greater increased crude risk was noted (13.67/1000 person-years and 4.91/1000 person-years, respectively). After adjustment of factors not considered to be on the causal pathway between PI/r use and CVD, only DRV was noted to be associated with excess CVD (IRR 1.59)/5 years. After adjustment for dyslipidemia and other causal factors for CVD, the still association held (IRR 1.53/5 years). The association also held when MI and CVA were evaluated separately, and when evaluating persons with high vs. low estimated 5-year CVD risk.
Dolutegravir (DTG) + Rilpivirine (RPV) May Be Non-inferior to 3 or 4 ARVS in Patients Who Are Virologically Suppressed
Given that persons living with HIV require lifelong ARV therapy, the HIV research community continues to investigate ARV regimen options to decrease ARV exposure. In this oral presentation, the results of 2 identical multicenter phase III non-inferiority trials were presented.8 Across both studies, 1024 participants who were on 3 or 4 ARVs, had an HIV-1 RNA of <50 c/ml for at least a year, and had no prior virologic failure were randomized to either continue their current regimen or be switched to a regimen of DTG and RPV. The primary endpoint was the proportion of patients with an undetectable VL at 48 weeks. In a pooled analysis of both studies, switching to DTG+RPV was non-inferior to continuing 3-4 ARVs at 48 weeks. One patient in the DTG+RPV arm developed an NNRTI resistance mutation (K101K.E); no integrase inhibitor mutations were noted. There were more discontinuation due to adverse events in the DTG+ RPV arm.
More about this year’s CROI conference, including webcasts for many presentations, can be found online: https://www.croiconference.org/
Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525-30.
Perfect JR, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 Update by the Infectious Diseases Society of America. CID. 2010; 50(3): 291-322.
Jarvis JN, et al. Ambition-CM: high-dose liposomal amphotericin for HIV-related cryptococcal meningitis. Abstract 82 presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed February 28, 2017.
Meintjes G, et al. Randomized controlled trial of prednisone for prevention of paradoxical TB-IRIS. Abstract 81LB presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA.
Rhew DC, et al. Association between protease inhibitor use and increased cardiovascular risk in patients infected with human immunodeficiency virus: a systematic review. Clin Infect Dis. 2003;37(7):959-72.
Ryom L, et al. Association between cardiovascular disease and contemporarily used protease inhibitors. Abstact 128LB presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA.
Llibre JM, et al. Phase III Sword 1&2: Switch to DTG+RPV maintains virologic suppression through 48 weeks. Abstract 44LB presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA.