Evolving controversies and challenges in the management of opportunistic infections in HIV-seropositive individuals

The British HIV Association, in association with the British Infection Association, has produced guidelines on the management of opportunistic infections in individuals living with HIV. Opportunistic infections remain a major clinical challenge emphasising the key role of early testing and getting individuals on antiretroviral therapy before their CD4 T-cell count drops to levels that put individuals at risk of opportunistic infection. We emphasise the changing pattern of opportunistic infections and the importance of considering what constitutes an opportunistic infection in the era of effective combination antiretroviral therapy as well as the increasing burden of geographically restricted infections. Key areas of when to safely stop prophylaxis against opportunistic infection and when to start antiretroviral therapy after treatment of an opportunistic infection are discussed.     

Pulmonary infections in the HIV-infected patient in the era of highly active antiretroviral therapy: An update

The highly active antiretroviral therapy (HAART) era began in 1996 when the combination of multiple antiretroviral agents was found to improve outcomes in HIV-infected patients. HAART has made a tremendous impact on the progression of HIV and on the morbidity and mortality associated with its opportunistic infections. HIV-positive patients who respond to HAART have a decreased incidence of opportunistic infections. Studies have documented close to a 50% decline in the incidence of pneumocystis pneumonia and bacterial pneumonia with the use of antiretroviral therapy. Primary and secondary prophylaxis for pneumocystis pneumonia can be discontinued in patients who show a sustained response to antiretroviral therapy. Unique to the HAART era, immune reconstitution syndrome is characterized by a paradoxical deterioration of a preexisting infection that is temporally related to the recovery of the immune system. Recently, more and more patients are being admitted for non-AIDS related illnesses in the HAART era.     

No news is good news: opportunistic infections

The 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was notable for not having any oral sessions on opportunistic infections. This is an indication of the enormous success of combination antiretroviral therapy, which has greatly reduced the occurrences of opportunistic infections. Hepatitis C was discussed at the conference, but it was treated as a co-morbid condition rather than an opportunistic infection. Two studies addressed the question of stopping pneumocystis prophylaxis in patients responding to antiretroviral therapy. Other issues discussed included mycobacterium avium complex (MAC), cytomegalovirus (CMV), and pyogenic bacterial infections.     

Gastroduodenal opportunistic infections and dyspepsia in HIV-infected patients in the era of Highly Active Antiretroviral Therapy

Background and Aim: Dyspeptic symptoms are frequently reported by human immunodefficiency virus (HIV)‐infected patients under highly active antiretroviral therapy. Whether opportunistic infections are a cause of dyspepsia is still unknown. In this study we prospectively compare the prevalence of gastrointestinal opportunistic infections in dyspeptic versus non‐dyspeptic HIV‐infected patients with advanced immunodeficiency. Patients and Methods: Six hundred and ninety HIV‐infected patients under highly active antiretroviral therapy underwent esophagogastroduodenoscopy with mucosal biopsies from the stomach and duodenum. Group 1: 500 patients (161 women, 339 men; mean age 38.8 years; mean CD4 count 154.3 cells/mm³ with dyspeptic symptoms such as epigastric pain, nausea, vomiting and fullness. Group 2: 190 patients (169 men, 21 women; mean age 40.7 years; mean CD4 count 171.6 cell/mm³) with no dyspeptic symptoms. Results: Group 1: Gastrointestinal opportunistic infections were observed in eight (1.6%), and non‐opportunistic parasites in two (0.4%), patients. They were: Cytomegalovirus (four patients), Cryptosporidium sp. (two patients), Schistosoma mansoni sp. (one patient), Strongyloides stercoralis (one patient) and Giardia sp. (two patients). In five patients esophagogastroduodenoscopy showed no mucosal lesions. Group 2: Giardia sp. was detected in two patients (1.1%: P = 0.07947). Conclusion: Gastrointestinal opportunistic infections were shown in a small number of HIV‐infected patients under highly active antiretroviral therapy with advanced immunodeficiency. Although gastrointestinal opportunistic infections were detected exclusively in the dyspeptic patient group, they could not be related to these symptoms, since the number of infected patients was not statistically significant. To correctly diagnose opportunistic infections, multiple biopsy specimens may be necessary even from normal‐appearing mucosa.     

IL-23 and IFN-gamma deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on highly active antiretroviral therapy

The pathogenesis of HIV infection and the susceptibility to opportunistic infections has been associated with poor type 1 cytokine production. In severely immunodeficient HIV patients who achieved increased CD4 T-cell counts on longterm highly active antiretroviral therapy, we observed reduced expression of IL-23p19 and IFN-gamma messenger RNA. Impaired IL-23-induced IFN-gamma production by memory T cells might thus contribute to opportunistic infections in a minority of patients with substantial CD4 T-cell recovery.     

Treatment of HIV-related tuberculosis—unresolved issues

Abstract:   Tuberculosis (TB) is one of the most common opportunistic infections among persons with HIV infection. However, there are uncertainties about both TB and HIV treatment regimens among patients with advanced immunodeficiency. On the TB treatment side, there are lingering concerns about whether patients with advanced immunodeficiency should have a more intensive regimen for TB treatment (longer duration, more frequent [daily] dosing and/or post-treatment isoniazid). The use of antiretroviral therapy among patients with TB and AIDS dramatically decreases the risk of death and other opportunistic infections. However, use of antiretroviral therapy during TB treatment is complicated by the need to coordinate the activities of the TB control program and the HIV care clinic, overlapping side-effect profiles of anti-TB and antiretroviral drugs, drug–drug interactions between the rifamycins and many antiretroviral drugs, and the occurrence of immune reconstitution inflammatory syndrome events. The combination of rifampin-based TB treatment and efavirenz-based antiretroviral therapy is clearly the best option for cotreatment of these two infections. However, there are a number of uncertainties about the optimal antiretroviral therapy if efavirenz cannot be used (because of intolerance, drug resistance, pregnancy or lack of an appropriate formulation in children). The competing risks of AIDS events and severe immune reconstitution inflammatory syndrome events raise uncertainties about the optimal timing of antiretroviral therapy during TB treatment. Despite all of these complexities, the treatment of HIV-related TB can be remarkably successful. I review these unresolved questions in the treatment of HIV-related TB and suggest studies to help resolve them.     

Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.     

Cessation of secondary prophylaxis in patients with cryptococcosis

Cryptococcal disease in HIV-positive individuals is usually a consequence of advanced immunosuppression. Treatment consists of long period of induction therapy followed by long-term secondary prophylaxis, usually with fluconazole. The introduction of highly active antiretroviral therapy has resulted in improvements in immunological function such that the cessation of primary and secondary prophylaxis against several opportunistic infections has become possible. We report our experience of the cessation of secondary antifungal prophylaxis in patients responding to highly active antiretroviral therapy.     

Up-regulation of TLR2 and TLR4 in dendritic cells in response to HIV type 1 and coinfection with opportunistic pathogens

The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.     

Summary of the 5th Conference on Retroviruses and Opportunistic Infections

Research highlights from the Fifth Conference on Retroviruses and Opportunistic Infections are presented in the following five areas: 1) major messages concerning AIDS treatment and outcomes; 2) research findings on new antiretroviral agents; 3) prevention and treatment of opportunistic infections; 4) research on HIV transmission routes and rapid test strategies for HIV; and 5) the cost of AIDS health care and resource allocation. Important information delivered at the conference includes research on CD4 cell response during acute retroviral syndrome and long-term prognosis, viral burden nadir predicting long-term antiviral success, opportunistic infections and viral burden under 5,000, impaired phosphorylation after prolonged AZT therapy, and successful salvage in patients failing indinavir. The most important observations of antiretroviral agents are discussed for the following drugs: amprenavir, efavirenz, abacavir, and adefovir. Additional research is summarized on the reduction in the frequency of opportunistic infections in the age of highly active antiretroviral therapy (HAART), including the frequency of resistance during treatment of CMV retinitis and the treatment of tuberculosis and viral burden. Tables include results from selected clinical trials of antiretroviral therapy and results from research on salvage regimens. Finally, evidence is highlighted revealing that the cost of hospitalization has been substantially reduced but is offset by pharmaceutical costs.     

Immune reconstitution and the consequences for opportunistic infection treatment and prevention

Effective antiretroviral therapy that suppresses HIV replication is associated with dramatic increases in CD4 counts. Recent evidence suggests that this CD4 cell increase is biphasic in nature, with an initial phase (in the first 2 to 3 months) that represents redistribution of lymphocytes into the periphery and a second phase that is associated with true immunologic recovery and reconstitution. Immunologically there is evidence of increase in naive T cells, recovery of in vitro responses to microbial antigens, and repair of the damaged diversity of T cells. Clinically, this immune recovery has been characterized by decreasing morbidity and mortality from opportunistic infections, an ability to treat previously intractable infections, immune-mediated syndromes, and increasing reports of the ability to discontinue primary and secondary prophylaxis. Although there are still unresolved questions about the completeness of the immune recovery, most available evidence suggests in most patients the degree of immune reconstitution with effective antiretroviral therapy is sufficient to be protective against most opportunistic infections, and ultimately additional antimicrobial prophylaxis will be unnecessary.     

Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia.

Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.     

Recurrence of Pneumocystis carinii pneumonia in an HIV-infected patient: apparent selective immune reconstitution after initiation of antiretroviral therapy

Although several studies have reported that it is safe to discontinue secondary Pneumocystis carinii pneumonia (PCP) prophylaxis in patients infected with HIV who experience a sustained immune response as a result of antiretroviral therapy, we describe a patient who developed recurrent PCP <3 months after discontinuing trimethoprim-sulfamethoxazole prophylaxis. He developed disease despite a sustained CD4 T-cell count above 200 cells/microL for more than 3 years while on antiretroviral therapy, as well as an apparent immune reconstitution against disseminated Mycobacterium avium complex (MAC) and Histoplasma capsulatum, for which he also discontinued therapy but without adverse effects. Thus, although increasing evidence continues to indicate that HIV-infected patients receiving combinations of antiretroviral therapies may regain specific immunity against opportunistic infections, our patient's experience suggests that this immune recovery may be selective and incomplete.     

The Spectrum of Atherosclerotic Coronary Artery Disease in HIV Patients

The incidence of HIV is on the rise. With the advent of antiretroviral therapy, the average life expectancy of HIV patients has increased by several decades, but the increasing life expectancy has shifted the spectrum of HIV-associated morbidity and mortality away from opportunistic infections and toward chronic medical conditions. In fact, coronary artery disease has become the leading cause of mortality in patients with HIV. The pathophysiology of atherosclerosis in patients with HIV is very complex, including direct endothelial damage from viremia, a heightened overall state of inflammation from immune activation, higher prevalence and contribution from traditional atherosclerotic risk factors, and direct effects from antiretroviral therapy itself. This review focuses on the patterns, predictors, and pathophysiology of atherosclerotic disease in patients with HIV. In addition, the risks and benefits of evidence-based highly active antiretroviral therapy are critically evaluated.     

艾滋病抗病毒治疗后机会感染的变化和分布状况

目的探讨艾滋病(AIDS)抗病毒治疗后机会感染疾病谱的变化及分布状况。方法采用回顾性分析的方法,对2006年9月-2008年12月期间,在郑州市第六人民医院接受门诊及住院治疗的128例HIV/AIDS病人,抗病毒治疗前后机会感染发生情况进行总结分析。结果 (1)128例HIV/AIDS病人中,高效抗反转录病毒疗法(HAART)治疗3-12月期间共发生100例次机会感染,主要为呼吸系统(46.09%)和消化系统(11.72%)感染,其中前4位机会感染是细菌性肺炎(29.69%)、肺结核(9.38%)、口腔念珠菌感染(7.81%)、带状疱疹(3.91%);与HAART治疗前相比,治疗后机会感染中细菌性肺炎、肺结核占绝大多数(86.46%),存在一定比例的口腔念珠菌感染和带状疱疹,AIDS晚期常见的机会感染如肺孢子菌肺炎、感染性腹泻及消耗综合征、中枢神经系统病变发病明显减少。(2)128例HIV/AIDS病人HAART治疗前机会感染发病率为80.47%,治疗后3-6月时下降至28.13%,治疗6-12月时为25.89%,3组相比差异有统计学意义(P<0.05)。HAART治疗后同时合并多种机会感染的病例减少。结论 HAART治疗后的机会感染发病率明显下降,机会感染疾病谱较治疗前有所不同,同时合并多种机会感染的几率减少。     

The impact of potent antiretroviral therapy on the characteristics of hospitalized patients with HIV infection

OBJECTIVE: Despite advances in antiretroviral treatment, a large number of HIV-infected patients still require hospitalization. This study describes the characteristics of HIV patients requiring hospitalization before and after the advent of potent antiretroviral therapies. METHODS: Information was collected on all HIV-positive patients admitted to the New York Hospital-Cornell Medical Center in New York City. Data was collected from 1 January through 30 June 1995, and during the same 6-month interval in 1997. RESULTS: In each time period over 1500 outpatients were receiving treatment for HIV infection. There was a significant decrease in the incidence of admission [60.4 per 100 patient-years (PY) in 1995, 28.8 per 100 PY in 1997], and length of stay (10 versus 8 days). The median CD4 cell count of all HIV-infected patients admitted to the hospital doubled: 37 x 10(6)/l in 1995 versus 80 x 10(6)/l in 1997. However, there was no significant change in the median CD4 cell count of patients diagnosed with opportunistic infections. The incidence of the most common diagnosis (bacterial pneumonia, 8.0 per 100 PY in 1995 versus 3.6 per 100 PY in 1997) and the most common opportunistic infection (Pneumocystis carinii pneumonia 7.6 per 100 PY in 1995 versus 2.4 per 100 PY in 1997) decreased significantly. CONCLUSIONS: Since the introduction of potent antiretroviral therapy, a significant decrease in the incidence of hospital admission and opportunistic infections has occurred. There has been a doubling of the median CD4 cell count of inpatients. There has been no significant change in the median CD4 cell count at which patients present with opportunistic infections.     

HIV/AIDS患者并发新型隐球菌脑膜炎的诊疗新进展

随着HAART时代的到来,HIV/AIDS患者中隐球菌病的发病率已经明显下降,但仍然是最常见的机会性感染之一。尤其是由新型隐球菌引起的脑膜炎,在全球仍有着很高的发病率和病死率。本文将就HIV/AIDS患者并发新型隐球菌脑膜炎的病原学、流行病学、发病机理、临床表现及治疗等方面的研究进展进行综述。     

Diagnosis of esophageal ulcers in acquired immunodeficiency syndrome.

The esophagus is one of the most common sites of gastrointestinal involvement in human immunodeficiency virus (HIV)-infected patients, with at least 30% of the patients having esophageal symptoms at some point during the course of HIV infection. Esophageal ulcers are commonly caused by infections such as cytomegalovirus (CMV) or may be idiopathic. The clinical presentation of the various causes of esophageal ulcers are similar; therefore, a thorough endoscopic and histological workup is imperative to make a diagnosis and, consequently, to provide appropriate therapy. The widespread use of more effective antiretroviral therapy appears to have led to a decline in gastrointestinal opportunistic disorders in patients with acquired immunodeficiency syndrome (AIDS), including those involving the esophagus. Unfortunately, there are several reports of resistance of HIV-1 to multiple antiretroviral agents, and thus it is possible we will observe an increase in various opportunistic disorders again. The aim of this article is to provide a practical approach to the clinical, endoscopic, and histopathologic evaluation of esophageal ulcers in patients with AIDS.     

An update on Cryptococcus among HIV-infected patients

Cryptococcus remains an important opportunistic infection in HIV patients despite considerable declines in prevalence during the highly active antiretroviral therapy era. This is particularly apparent in sub-Saharan Africa, where Cryptococcus continues to cause significant mortality and morbidity. This review discusses the microbiology, epidemiology, pathogenesis and clinical presentation of cryptococcal infections in HIV patients. Additionally, a detailed approach to the management of cryptococcosis is provided.