The case highlights a number of important issues.

The clinical history of initiating HAART and anti-TB in a severely immunosuppressed individual who subsequently develops fever, malaise, SOB and worsening infiltrates is very suspicious for an immune reconstitution with inflammation syndrome (IRIS or "paradoxical response"). This is usually manifested within weeks of starting HAART and occurs in up to one third of TB patients with HIV who are administered HAART. A high viral load and low CD4 count at the time of presentation seem to be risk factors. This reaction is attributed to strengthening of the hosts delayed immune response by the therapy. It is felt that it may be possible to minimize this reaction as well as reduce the risk of drug related reactions early on in the TB treatment; by delaying the initiation of antiretroviral therapy 6-8 weeks after start of anti-TB treatment.

There are no well-performed clinical trials published in the literature on how to best manage these cases when they arise, however important points include:

1. This is a diagnosis of exclusion. Therefore other opportunistic pathogens must be sought such as PCP, CMV, as well as bacterial and fungal organisms. We would recommend pan-culturing the patient and if clinically stable, would perform a bronchospy with lavage and biopsy.

2. If no other explanation for these symptoms is found, then the management of IRIS is essentially supportive care. We recommend continuing HAART in most cases unless the patient is clinically unable to tolerate the symptoms. In addition, steroids or NSAID have been shown to decrease the inflammatory response in some patients. The decision must be individualized as the treatment may be harmful if other undiagnosed pathogens are present or if the patient is not on adequate TB therapy.

Of note, it is unclear why this patient is on a combination of Atripla and Sustiva. We would recommend stopping the Sustiva. In addition, we discourage the use of Rifampin in HIV patients on HAART and would recommend introducing Rifabutin at 450 mg/day or 600 mg TIW if the Atripla is continued. If HAART is stopped, then Rifabutin should be dosed at 300 mg /day. Rifabutin is an appropriate choice over standard Rifampin as it has fewer p450 interactions.

3. The elevated liver enzymes may be a drug reaction, may be unrecognized TB of the liver or may reflect the systemic inflammatory response that accompanies IRIS but other etiologies should always be ruled-out. Hep ABC serology should be performed along with an ultrasound of the liver. INH, RIF and PZA can all cause drug-induced liver injury and medications should be stopped when the AST level is three times the upper limit of normal in the presence of symptoms or five times the upper limit of normal in the absence of symptoms. It is estimated that 15-20% of patients on RIPE will develop an asymptomatic increase at some time during the course of therapy.

If the above work-up is negative, drug-induced hepatitis is likely. There are a number of ways in which medications can be re-introduced. In this case the PZA does not need to be part of the regimen as he is pansensitive and has received two months of four drugs. At this time, a relative liver-sparing regimen can be reintroduced combining Rifabutin, EMB and a fluoroquinolone until the patient is more clinically stable and the LFTs have normalized.

Given the complexity of this case, I have attached some articles for your review and would be happy to discuss any further questions or issues as they arise.