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Immediate ART After an OI: Are We There Yet?

Experts explain how they would approach ART initiation in a newly diagnosed patient with cryptococcal meningitis.

A 42-year-old man was admitted to the hospital with fever, headache, and confusion. A diagnosis of cryptococcal meningitis was made, and he was started on amphotericin/5FC. To bring elevated intracranial pressure (ICP) into the normal range, he underwent three lumbar punctures during the first 5 days of hospitalization. HIV testing performed on admission was positive, and additional data returned showing a CD4 count of 15 cells/mm³ and a viral load of 380,000 copies/mL. A resistance genotype showed no resistance mutations. After 5 days of treatment, the patient improved significantly compared with when he was admitted (the confusion cleared), but he was still complaining of headache, photophobia, and poor appetite. The amphotericin/5FC treatment was associated with a rise in serum creatinine levels from 0.9 to 1.5 mg/dL, and he required daily potassium supplementation.

The patient works part-time at a local restaurant. He is sexually active with men and states that an HIV test done approximately 5 years before admission was negative. He acknowledges intermittent use of crystal methamphetamine and cocaine. Before this hospitalization, he was taking no prescribed medications regularly. He has no health insurance. During discussions with a hospital social worker, he said he is terrified that he will die from AIDS-related complications.

What would you tell him about his prognosis? When would you start antiretroviral therapy (ART)? Which agents would you use?

Response 1

— Philip Grant, MD, and Andrew Zolopa, MD

Long-term prognosis of cryptococcal meningitis in AIDS has improved significantly in the era of potent ART. Early mortality in cryptococcal meningitis is reported to be between 6% and 15% (AIDS 2006; 20:2183, N Engl J Med 1992; 326:83, Lancet 2004; 363:1764, and Clin Infect Dis 1999; 28:82), but this patient’s response to therapy makes an early death from cryptococcal infection unlikely.

The optimal timing of ART initiation in patients with acute opportunistic infections (OIs) has been controversial. Delaying initiation of ART has been associated with HIV disease progression (AIDS 2002; 16:75), but starting it early has been associated with an increased incidence of immune reconstitution inflammatory syndrome (IRIS; AIDS 2005; 19:399).

In ACTG A5164, 282 patients with acute OIs were randomized to immediate versus deferred initiation of ART (Abstract 142, 15th Retrovirus Conference, 2008). At study entry, 63% of patients had Pneumocystis jirovecii pneumonia, and 12% had cryptococcal meningitis. Median time to ART initiation after starting OI therapy was 12 days in the immediate-treatment arm versus 45 days in the deferred-treatment arm. At 48 weeks, 14% of patients in the immediate-treatment arm died or had new serious OIs, compared with 24% of patients in the deferred-treatment arm (P=0.04). Rates of IRIS did not differ between the two arms. The study was not powered for subgroup analyses based on presenting OI, but rates of IRIS and other complications did not appear to be increased among patients with cryptococcal meningitis in the immediate-treatment arm. Based on these results, we would recommend starting antiretrovirals as early as clinically feasible — in this case, at day 5.

A boosted PI–based regimen is often initiated in patients with advanced disease, given the perceived paucity of data for efavirenz-based therapy in this setting. However, increasing evidence suggests that the efficacy of efavirenz-based regimens is at least equivalent to that of boosted PI–based regimens, even in advanced disease (N Engl J Med 2008; 358:2095). Although boosted PI–based regimens may lead to a larger increase in CD4-cell counts, randomized trials have shown that virologic outcomes associated with efavirenz regimens are at least equivalent to those associated with PI-based regimens.

Given this patient’s wild-type genotype, we would initiate efavirenz/FTC/tenofovir (Atripla) based on its ease of administration. Early studies of raltegravir in treatment-naive patients have shown intriguing rapid declines in viral load (J Acquir Immune Defic Syndr 2007; 46:125), but further study is needed before any of the newer generation of medications can be recommended for this population.

Response 2

— Raphael J. Landovitz, MD

The decision to initiate or defer ART in the context of an acute OI is a complex one. Restoration of immune competence is paramount to OI recovery and is useful for avoiding subsequent OIs (Clin Infect Dis 2000; 30:710 and Clin Infect Dis 2000; 30:S5). However, the benefits of early ART are tempered by overlapping toxicities and by the potential for IRIS.

A recent retrospective study in patients with cryptococcal meningitis found no survival difference with earlier ART initiation (J Acquir Immune Defic Syndr 2008; 48:508). In contrast, an ACTG randomized trial (A5164) demonstrated a survival advantage when ART was started within the first 2 weeks after OI diagnosis (Abstract 142, 15th Retrovirus Conference, 2008). However, most OIs in this well-designed study did not involve the central nervous system (CNS), and clinicians continue to be concerned that IRIS in the context of a CNS-related OI might be more severe than IRIS outside the CNS. IRIS has been reported in approximately 30% of patients starting ART in the setting of cryptococcosis (Clin Infect Dis 2005; 40:1049).

To help determine this patient’s risk for IRIS-related adverse outcomes, I would evaluate for the presence of cryptococcomas (masses attributable to Cryptococcus) in the posterior fossa, using magnetic resonance imaging, and would also make sure that either elevated ICP had resolved or that cerebrospinal fluid had drained adequately via internal or external shunting. Assuming no cryptococcomas, I would favor starting ART 10 to 14 days after OI treatment was initiated. In addition to the potential survival advantage, such timing should allow us to tease out attribution of any toxicity that might occur with the antifungals or antiretrovirals.

Any of several antiretroviral options would be appropriate for this patient, given that his HIV does not appear to harbor significant resistance mutations. However, with a CD4 count <50 cells/mm³ and a viral load >100,000 copies/mL, he is in the highest risk category for further OIs and death. Regimens that have a proven track record in such patients include dual nucleosides with either efavirenz or a boosted PI. Although some providers are squeamish about using efavirenz-based therapy in such patients because of the perceived fragility of the NNRTI class, the clinical data, including the findings of ACTG A5142, support the superior efficacy of efavirenz-based regimens in this setting (N Engl J Med 2008; 358:2095). For cases in which CNS toxicity, potential for teratogenicity, transmitted resistance, or rash are of great concern, a boosted PI such as ritonavir-boosted darunavir or lopinavir/ritonavir might be an appropriate alternative. For this particular patient, for ease of dosing and tolerability, I would favor the once-daily fixed-dose combination tablet containing tenofovir, FTC, and efavirenz (Atripla). I would also refer this patient to appropriate mental-health and substance-abuse programs, because of his ongoing drug use, which could contribute to poor medication adherence (J Acquir Immune Defic Syndr 2007; 46:S64) and, ultimately, to premature death.

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Dr. Grant is a Fellow in the Division of Infectious Diseases at Stanford School of Medicine. Dr. Zolopa is Associate Professor of Medicine at Stanford School of Medicine and was the principal investigator of ACTG 5164.

Dr. Landovitz is Assistant Professor in the Division of Infectious Diseases, Center for Clinical AIDS Research and Education, at University of California, Los Angeles.

Published in Journal Watch HIV/AIDS Clinical Care July 28, 2008

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