The literature on the clinical efficacy and safety of anti-TNF agents in HIV-infected individuals is extremely limited, with only a few anecdotal case reports to guide us. However, the theoretical risks and benefits of anti-TNF therapy in this immunosuppressed population can be extrapolated from a number of in vitro and in vivo studies investigating the role of TNF-a in HIV infection, and the effects of TNF blockade on HIV RNA levels and CD4 counts.
TNF-a is a pro-inflammatory cytokine that functions as a central mediator of inflammation and immune regulation. Not surprisingly, given its role in host defense against viral infections, TNF-a levels have been found to be elevated in HIV+ patients,, reflecting immune system activation. However, a number of in vitro studies have demonstrated deleterious effects of TNF-a, thereby implicating it in the pathogenesis of HIV. TNF-a has been shown to increase destruction of infected CD4+ lymphocytes and up-regulate HIV replication in HIV-infected cells in vitro,,, while anti-TNF-a antibodies have been shown to suppress HIV-1 production in chronically infected T lymphocytic cell lines. Moreover, monocytes exposed to HIV proteins can be induced to produce TNF-a, thus linking overproduction of TNF-a with HIV replication, and potentially HIV disease progression.
Clinically, TNF-a levels have been positively correlated with HIV-RNA levels, and down-regulation of TNF-a has been demonstrated upon initiation of highly active antiretroviral therapy (HAART). Persistence of TNF-a after initiation of HAART therapy has also been suggested to correlate with virologic and immunologic treatment failure as well (defined as detectable HIV RNA after 52 weeks of therapy and significant decrease in CD4 lymphocytes, respectively). Specific effects of TNF blockade on HIV RNA and CD4 counts have been studied in a number of clinical trials using thalidomide and pentoxifylline, weak inhibitors of TNF-a production, as well as etanercept and cA2, a chimeric humanized monoclonal antibody against TNF-a. Wallis et al found that pentoxifylline decreased plasma HIV RNA levels in a group of untreated HIV+ patients with pulmonary TB, but had no proven effect on TNF-a, CD4 cell count or patient survival. In contrast, Jacobson et al found that thalidomide unexpectedly increased HIV RNA and plasma concentrations of TNF-a. Sha et al studied the effect of etanercept on TNF-a and other cytokines in HIV-infected patients on HAART receiving IL-2 injections (previously shown to increase CD4 lymphocytes when administered in HIV patients with CD4 counts >200/mm3). Etanercept was given as a single 10 mg intravenous infusion, and was not found to have a significant effect on CD4 count or viral load, although all patients at baseline started out with undetectable or low-level viremia. The effect on TNF-a bioactivity could not be assessed in this study. Lastly, Walker et al investigated the effect of cA2 on levels of TNF-a, CD4 cells and HIV RNA in six HIV+ patients with CD4 counts below 200/mm3. Two infusions of 10mg/kg were given 14 days apart, resulting in only transient decreases in TNF-a levels, but no significant effect on CD4 cell counts or plasma HIV RNA levels over the 42 day period.
Thus far, there have only been two case reports on the use of anti-TNF agents in HIV+ patients with rheumatic disease. Aboulafia et al reported the use of etanercept, 25 mg SQ twice weekly, in a 45 year old HIV-infected male on HAART who developed severe skin disease and disabling psoriatic arthritis. The patient had at baseline a CD4 count of 20/mm3, viral load 14,000 copies/mL, ESR 125, and radiographs of hands and feet that were consistent with psoriatic arthropathy. Within three weeks of initiating etanercept, the patient had dramatic improvement in skin and joint manifestations, and his CD4 count and HIV viral load remained stable throughout the six month treatment course. However, his clinical course was complicated by recurrent polymicrobial bacterial infections, both while on therapy and in the subsequent four months after therapy had been discontinued, which ultimately led to the patient's demise. Gaylis reported the safe use of infliximab (3mg/kg every 6-7 weeks) in a 41 year old HIV+ male on HAART with Reiter's syndrome refractory to corticosteroids and methotrexate. The patient had at baseline a CD4 count of 770 cells/mm3 and a viral load of <500 copies/mL. With infliximab, he experienced significant resolution of all symptoms attributed to his Reiter's syndrome, and was able to discontinue use of daily corticosteroids. No adverse events were reported during the 18 months that the patient received infusions, and the pt's CD4 count and viral load remained stable.
Because TNF-a plays an important role in host defense against microorganisms, there is obviously concern that TNF blockade, even in immunocompetent hosts, might result in an increased frequency or severity of infections. Reactivation of tuberculosis (TB) is a well-recognized complication, and this specific issue has been indirectly addressed in a phase 1 study investigating the role of etanercept as adjunctive therapy for HIV+ patients with pulmonary TB. 16 HIV+ patients with CD4 counts >200/mm3 and active pulmonary TB were treated with etanercept 25 mg subcutaneously twice weekly for a total of eight doses, in conjunction with TB therapy. When compared to controls with similar CD4 counts, patients receiving etanercept were, on average, able to develop negative sputum cultures more rapidly (p=0.05). However, two patients had increases in sputum AFB counts, warranting discontinuation of therapy. Etanercept was discontinued in a third patient due to a rise in HIV RNA and worsening of cough and dyspnea, ultimately attributed to pulmonary embolism. Of the remaining patients, there were no statistically significant differences in CD4 counts or plasma HIV RNA levels between the treatment and control groups. The authors concluded that etanercept could be safely administered during the initial treatment of pulmonary TB. (This is discussed in the Ask the Expert response to: In RA patients unresponsive to several DMARDs but who are PPD+ although the chest X-ray is negative, how long should INH prophylaxis be maintained before initiating an anti-TNF agent? Is anakinra safe to use in patients with a positive PPD?)
In summary, based on the data from limited case reports and a number of in vitro and in vivo experiments, it is reasonable to conclude that anti-TNF agents can be used with great caution in HIV+ patients with significant morbidity from a TNF-a-mediated illness. Other patient factors that may influence therapy include pre-treatment CD4 counts, HIV RNA levels, and coexisting hepatitis B and C infection. If anti-TNF therapy is initiated, strict adherence to current guidelines, such as PPD placement and pneumococcal vaccination, should be observed to minimize potential infectious complications.
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