Abstract

We observed that 0 of 19 patients with human immunodeficiency virus type 1 (HIV-1) infection, including those with acquired immunodeficiency syndrome (AIDS), who were hospitalized together and who had close contact with 95 patients with severe acute respiratory syndrome (SARS) on the same hospital floor contracted SARS, whereas 6 of 28 medical workers who served on this floor contracted SARS while caring for these patients. Our investigation found that most of the patients with HIV-1/AIDS were receiving treatment of highly active antiretroviral therapy (HAART) during hospitalization. Coincidentally, a research group from Hong Kong recently reported that patients with SARS who received treatment with the anti—HIV-1 drug lopinavir-ritonavir experienced significantly better clinical outcomes than did those who did not receive lopinavir-ritonavir. On the basis of these observations and studies, we propose that HAART should be considered for patients with SARS and their close contacts when the SARS epidemic reemerges.

Two of the epidemiological characteristics of severe acute respiratory syndrome (SARS) are nosocomial infection and infection of medical workers who directly care for patients with SARS [1, 2]. However, in Guangzhou, the capital city of Guangdong province in China, we observed that none of the 19 patients with HIV-1/AIDS who were hospitalized together with 95 patients who had SARS on the same hospital floor became infected with the SARS virus [3]. Our investigation showed that there was cross-contact between patients and medical staff in the AIDS and SARS wards on this floor. Against the advice of medical personnel, patients with HIV-1/AIDS and those with SARS shared corridors and had contact over short distances: they walked past and sometimes talked with each other every day during a period of 1 week to 3 months (1 week to 1 month for 4 patients and 1–3 months for 15 patients who shared the corridors with a total 95 patients with SARS). Other details of this investigation, including the floor plan and ward distribution, are described in our previous report [3]. Most of the patients with HIV-1/AIDS were receiving HAART during hospitalization. None of these patients with HIV-1/AIDS had evidence of infection with the SARS virus (based on the presence of antibodies to the SARS virus) even 2 weeks after the last patient with SARS was discharged from the floor. However, 6 of 28 members of the medical staff who directly served on this floor contracted SARS [3].

We hypothesized that existing infection with HIV-1 might interfere with replication of the SARS virus in the same host, such that HIV-1—infected patients did not become coinfected with SARS virus. We also postulated that treatment of patients with HIV-1/AIDS with HAART might prevent the development of SARS [3]. On the basis of our observations, we advised the use of HAART to prevent and treat infection with the SARS virus. This advice was communicated to authorities in mainland China during April and May of 2003, during which time SARS was epidemic in this area.

Coincidentally, a research group from Hong Kong recently reported the results of a clinical trial of anti—HIV-1 drugs for treatment of SARS [4]. In that study, 75 patients with SARS who were treated with a formulation of 2 HIV-1 protease inhibitors, lopinavir and ritonavir (Kaletra; Abbott), in addition to a standard treatment protocol adopted by the hospital authority, were matched with control subjects retrieved from the hospital authority SARS central database. The matching was done with respect to age, sex, the presence of comorbidities, lactate dehydrogenase level, and the use of pulse steroid therapy. The 75 patients treated with lopinavir-ritonavir were further divided into 2 subgroups for analysis: those who received lopinavir-ritonavir as initial treatment (44 patients), and those who received lopinavir-ritonavir as salvage therapy (31 patients). These groups were compared with matched cohorts of 634 and 343 patients, respectively. The Hong Kong research group found that the use of lopinavir-ritonavir as initial treatment was associated with a lower overall mortality rate (2.3%) and intubation rate (0%), compared with a matched cohort of subjects who did not receive lopinavir-ritonavir (15.6% and 11.0%, respectively; P < .05). However, the subgroup of patients who received lopinavir-ritonavir as salvage therapy showed no difference in the overall mortality rate or in rates of oxygen desaturation and intubation, compared with the matched cohort [4], suggesting that early use of lopinavir-ritonavir has efficacy for the treatment of SARS.

Before the researchers in the Hong Kong study published their results, the corresponding author, Dr. K. Y. Yuen, presented the preliminary data at the 2003 Prevention and Cure of SARS Seminar held in Guangzhou in September [5]. At this conference, Yuen mentioned that they found a suppressing effect on the SARS virus resulting from use of a single drug (either lopinavir or ritonavir), and they then found that putting both drugs together had a synergistic role in inhibition of the virus in vitro. However, they did not study the drug synergy in their subsequent clinical trial. A small dose of ritonavir has no treatment efficacy, but when used in the formulation of lopinavir-ritonavir, it inhibits the metabolism of lopinavir, thus prolonging its effective plasma concentration. This means that the antiviral activity of lopinavir-ritonavir is attributable to lopinavir in vivo [6]. Combination therapy is the basis of the principal of treatment for HIV-1 infection, and a combination of potent drugs may be even more efficacious for treatment of SARS than use of single drugs. This was implied in our observational study [3], in which the patients with HIV-1/AIDS (most of whom were receiving HAART) did not become infected with SARS virus while hospitalized together with patients with SARS. Furthermore, on the basis of our observation, we do not recommend the use of a protease inhibitor, but rather use of a reasonable drug combination, just like a regimen used for treatment of HIV-1/AIDS, because only 2 of our patients received a regimen that contained a protease inhibitor (indinavir) [3]. Therefore, we propose that HAART, which has been shown to be effective for the treatment of HIV-1/AIDS, should be considered for use in the prevention and treatment of SARS.

With respect to HIV-1/AIDS, HAART has been used with positive results for the treatment of infection. However, the use of HAART may have even more significance for the prevention of SARS. SARS is a self-restricted, acute infectious disease and, with the right supportive care and symptom-related treatment, >90% of patients with SARS can be cured. The potential of HAART as a treatment for SARS lies in its ability to increase the cure rate among patients with clinically severe cases. With respect to more moderate clinical presentations, treatment with HAART may reduce the symptoms of SARS and shorten the course of illness. In mild cases, treatment with HAART may have limited impact, but it may nonetheless play a role in terms of public health. Treatment of patients with SARS can be viewed as a means of potentially decreasing the virus load and increasing the CD4+ T cell count, which may reduce the rate of transmission of the SARS virus [7]. HAART treatment for “super-spreaders” [8] may be of significant importance in altering the epidemiology of virus spread. We propose that, if a diagnosis of SARS is established during the acute phase of viral replication, HAART may be administered to reduce the probability of viral transmission. Moreover, preventive treatment with HAART may also impact transmission of the virus to medical personnel who have close contact with patients with SARS, especially after accidental exposure during clinical procedures.

During the 2003 Prevention and Cure of SARS Seminar (Guangzhou), experts debated the expenses and side effects associated with administration of HAART to patients with SARS. It is our opinion that, when used for either the prevention or the treatment of SARS, HAART is affordable for most individuals. For preventative treatment of close contacts, such as medical personnel, 1–2 weeks of therapy should be sufficient, whereas 2–3 weeks of therapy may be necessary for patients with SARS during the acute phase of viral replication. This duration of therapy is not comparable to that required for the treatment of HIV-1/AIDS, for which it may extend for the lifetime of the patient. Because the treatment of SARS is short-term, many of the side effects associated with the use of HAART, such as development of kidney stones, lipodistrophy, diabetes, and peripheral neuropathy, are unlikely to pose a significant problem. The most common side effect of short-term use of HAART is an early gastroenteric response, but short-term treatment is usually well tolerated by most patients.

Despite data suggesting the potential efficacy of HAART, we do not advocate its routine use for the prevention and treatment of SARS at this time. Instead, we suggest continued cooperation between SARS and AIDS clinicians and research scientists, both nationwide and internationally, to design and conduct clinical trials (or at least a trial that includes a comparison of a protease inhibitor—containing regimen with a protease inhibitor—free combination) in a timely manner in accordance with Good Clinical Practices. It is imperative to determine whether effective regimens of HAART can be developed for SARS so they may be quickly applied during the early stages of an epidemic. Thus, SARS may be rapidly and effectively controlled should it re-emerge in the future—a possibility considered likely by many SARS experts.

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