pre-ART Era Research Articles

Clinical and Immunologic Predictors of Death After an Acute Opportunistic Infection: Results from ACTG A5164

Background: In the pre–antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. Objective: To determine clinical and immunological predictors of death after an OI. Methods: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. Results: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. Conclusions: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

Heart failure in patients with human immunodeficiency virus infection: epidemiology, pathophysiology, treatment, and future research.

With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 (HIV-1) infection has become a chronic disease with longer life expectancy.1 The HIV Outpatient Study showed that, with the addition of antiretroviral therapy (ART), mortality declined from 29.4 to 8.8 per 100 person-years.2 More recent data indicate that the proportions of patients expected to survive 5, 10, and 15 years after seroconversion in the HAART era are 99%, 93%, and 89%, respectively.3 With the increased life expectancy and decreased morbidity from opportunistic infections, the recognition and importance of chronic complications associated with HIV-1 infection are becoming more evident. Cardiac diseases are common complications found in these patients. The spectrum of heart diseases varies significantly between developed and developing countries and, in developed countries, between pre-HAART and post-HAART eras.4 Among them, HIV-associated cardiomyopathy, broadly defined as a decreased left ventricular (LV) ejection fraction or dilated LV by imaging studies, with or without symptoms of heart failure, is currently recognized as a major long-term complication of HIV-1 infection in developing countries; however, it is still prevalent in developed countries.4 Many questions regarding its pathogenesis and treatment remain unanswered. The epidemiology of HIV-associated cardiomyopathy has changed since the first report in 1986.5 The advent of HAART has significantly altered both the incidence and prevalence of this disease, and the definition of HIV-associated cardiomyopathy has also evolved from one of primarily systolic dysfunction to now reflect the growing recognition of diastolic dysfunction in these patients. The incidence of HIV-associated cardiomyopathy is difficult to ascertain because very few studies actually evaluated this measure. In the pre-ART era, HIV-associated cardiomyopathy was defined as symptomatic, systolic dysfunction with a dilated LV and was seen almost exclusively in patients with advanced HIV disease and AIDS. These older studies, …

Isolated penile Kaposi’s sarcoma in a HIV-positive patient stable on treatment for three years

Kaposi's sarcoma (KS) is an AIDS-defining condition. Typically, KS affects the skin with or without visceral involvement. The extensive use of antiretroviral therapy (ART) has decreased the incidence of KS amongst the HIV-positive population. We report a case of a 40-year-old man with HIV-1 infection with CD4 count of 551 cells/mm(3)and an undetectable viral load who presented with two skin-coloured KS lesions on the prepuce of the penis. Diagnosis was confirmed by histopathology. He had been commenced on ART three years earlier with a nadir CD4 count of 255 cells/mm(3) He had achieved and maintained viral suppression since commencing ART. The patient was initially treated with cryotherapy and 5% imiquimod as the lesions were presumed to be warts. The lack of response to treatment prompted further investigation. We carried out a literature search of published cases of penile KS over the past 10 years. The majority of articles regarding penile KS were published in the pre-ART era and involved patients with AIDS. Over the past 10 years, published cases of penile KS have almost exclusively been in HIV-negative men. We found 10 published cases of penile KS in HIV-negative men and only one other published case of penile KS in a HIV-positive man, who had severe immune suppression with CD4 count below 200 cells/mm(3) This is the first case report to describe a HIV-positive patient stable on ART with a CD4 count above 200 cells/mm(3)and suppressed HIV-1 viral load, to develop two KS lesions on the penis. Clinicians have to remain suspicious of penile lesions and appreciate the crucial role a biopsy with histopathological analysis plays in confirming a diagnosis. In addition, this case illustrates that unusual presentations of KS can still occur in treated HIV-positive patients with sustained immune recovery.

Neurologic Complications of HIV-1 Infection and Its Treatment in the Era of Antiretroviral Therapy

Neurologic complications of HIV infection are unfortunately common, even in the era of effective antiretroviral treatment (ART). The consulting neurologist is often asked to distinguish among neurologic deterioration due to opportunistic infection (OI), immune reconstitution, or the effect of the virus itself, and to comment on the role of immunomodulatory agents in patients with HIV infection. Additionally, as successful virologic control has extended the life span of patients with HIV infection, neurologists are called upon to manage long-term complications, such as neurocognitive disorders and peripheral neuropathy. Despite the use of ART, significant numbers of patients continue to be affected by HIV-associated neurocognitive disorders, although with milder forms compared to the pre-ART era. Regimens of ART have been ranked according to CNS penetration and are being studied with regard to neuropsychological outcomes. Nucleoside analogs with the greatest potential for peripheral neurotoxicity are no longer considered first-line agents for HIV treatment. Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has the greatest frequency of neurologic side effects among newer ART regimens. The spectrum of clinical manifestations of immune reconstitution inflammatory syndrome (IRIS) continues to grow, including IRIS without underlying OI. A greater understanding of pathophysiology and risk factors has shown that while HIV should be treated early to prevent severe immunocompromise, delayed initiation of ART may be helpful while treating OIs. This article reviews the neurologic complications of HIV infection, or its treatment, most commonly encountered by neurologists.

CMV Retinopathy in the Antiretroviral Therapy Era: Prevention, Diagnosis, and Management

Before the advent of antiretroviral therapy (ART), CMV retinitis was a common, debilitating opportunistic infection in the HIV-infected population. ART has had such a favorable impact on the prevention and management of CMV retinitis that it can be considered in some ways to be CMV therapy. Currently available CMV directed antiviral therapies are quite successful at limiting vision loss, but in resource limited settings there is still significant morbidity associated with the disease. This review summarizes the pathology, diagnosis, clinical course and treatment of retinitis in the pre-ART era to provide context for the contemporary clinical scenario, and highlights current management strategies. Important questions concerning host correlates of susceptibility and ideal therapy in the context of drug resistance are also briefly reviewed.

How can this be? Preventing death in patients with HIV-associated tuberculosis [Editorial

How can this be? Preventing death in patients with HIV-associated tuberculosis [Editorial

Neuro-AIDS in the developing world

Despite 20 years of development, no practical vaccine for HIV is available, and HIV/AIDS remains a major health problem, with 33 million people infected and 2.6 million new infections in 2009. The infection is most prevalent in sub-Saharan Africa. Although rates of infection remain high, developments in antiretroviral regimens and changes in public health policy worldwide have significantly increased lifespans and changed the landscape of HIV complications, including the neurologic complications. Prior to the availability of highly active antiretroviral therapy (HAART), neurologic disease was the heralding manifestation of AIDS in 7%–20% of patients and prevalence rates of neurologic infections varied from 39% to 70%. Following the introduction of HAART, neurologic disease declined significantly, particularly rates of CNS opportunistic infections (OI). Nonetheless, AIDS-related neurologic disease continues to represent a significant burden for developing countries. The spectrum of AIDS-related disease in many developing countries appears to parallel that reported in the pre-HAART era. In one study from Thailand conducted over 2 years, 2007–2008 inclusive,1 the most common CNS disorders in order of frequency were cryptococcal meningitis (37.8%), tuberculosis (TB) (35.8%), toxoplasmosis (12.8%), progressive multifocal leukoencephalopathy (4.1%), varicella zoster meningitis (2.7%), pneumococcal meningitis (1.4%), herpes simplex meningitis, and Epstein-Barr–related primary CNS lymphoma. Similarly, in South Africa, the CNS disorders observed have mirrored those seen in the pre-ART era in developed countries; a phenomenon attributed to the relative unavailability of antiretroviral therapy.2 Although incompletely investigated, it is widely believed that antiretroviral therapy has reduced the …

Yet Another Reason to Treat HIV Infection

Antiretroviral therapy (ART) has allowed a cohort of children who were perinatally infected with human immunodeficiency virus (HIV) to reach early adulthood, but their risk of death, non-AIDS-defining infections, cancers and organ failure remain elevated compared with uninfected populations [1]. Although ART dramatically improves the survival of infants [2] and children [1] and appears to improve the growth and neurologic function when initiated in older children [3, 4], less is known about the optimal time to initiate ART in older, asymptomatic children to prevent indolent HIV-associated morbidities, including loss of cognitive functions. The recommended CD4 cell count at which to start ART in adults and adolescents has been progressively revised upward [5]; however, this threshold remains controversial, and resulted in the split judgment by the 2011 Department of Health and Human Services panel on whether to recommend ART for all adults [5]. Current World Health Organization guidelines recommend the use of adult immunologic criteria (CD4 cell count, ,350 cells/lL) to determine when to initiate ART in children .5 years of age [6]. This leaves many relatively asymptomatic HIV-infected children with moderately decreased CD4 T-cell counts untreated, which could place them at risk for HIV-associated morbidity. (Normal CD4 cell counts in children 5–12 years of age range from 980 to 1200 cells/lL [7, 8]). In this issue of Clinical Infectious Diseases, Ruel et al [9] present a casecontrol study that demonstrates neurocognitive and motor dysfunction in ‘‘asymptomatic’’ HIV-infected children 6–12 years of age who do not qualify for ART. Their findings suggest that the World Health Organization guidelines do not capture early neurologic disease and provide a rationale to explore whether earlier ART would benefit these children. In children, progressive HIV encephalopathy (PHE) is a severe, potentially fatal, AIDS-defining illness that was common in the pre-ART era. It is defined as failure to achieve developmental milestones, or loss of previously acquired developmental milestones, impaired brain growth, and acquired symmetrical motor deficits (manifested by $2 of the following: paresis, pathologic reflexes, ataxia or gait disturbance) [10]. In the pre-ART era, the prevalence of PHE was 30%–50% [11]. With the use of ART, symptoms of those affected by PHE generally have improved, fatalities have become uncommon, and the incidence of PHE has dropped 10-fold [4, 11]. The study by Ruel et al carefully assessed neurocognitive and motor function in HIV-infected African children who did not qualify for ART and who were not considered encephalopathic by their referring physicians. The study used neurocognitive tests (Test of Variables of Attention [TOVA]; the Kaufman Assessment Battery for Children, 2nd edition [KABC-2]; and the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition [BOT-2]) to detect impairments in attention deficit and impulsivity, cognition, and motor function, respectively. The study does not provide an estimate of the prevalence of neurocognitive impairment but identifies subtle population-level differences between HIV-infected and uninfected children. This study is noteworthy because it suggests that, unlike PHE, which is rare in the era of ART, subtle neurocognitive and motor impairments affect a significant proportion of apparently asymptomatic HIV-infected children who do not yet qualify for ART. Unfortunately, the large-scale administration of the neurocognitive tests used by Ruel et al to prompt ART initiation is unrealistic in low resource settings owing to the time, space, and trained personnel needed for testing. Ideally, biomarkers and/or simple tests would identify early symptoms of neuropathology and serve as tools to monitor children who do not qualify for ART. Received 1 December 2011; accepted 9 December 2011. Correspondence: Lisa M. Frenkel, MD, Department of Pediatrics, Laboratory Medicine and Global Health, University of Washington, Children's Hospital and Research Institute, 1900 Ninth Avenue, Seattle, WA 98101-1304 (lfrenkel@uw.edu). Clinical Infectious Diseases The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/cid/cir1041

Restricted Kaposi’s Sarcoma (KS) Herpesvirus Transcription in KS Lesions from Patients on Successful Antiretroviral Therapy

ABSTRACTKaposi’s sarcoma (KS) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8). KS is an AIDS-defining cancer, and it is changing in the post-antiretroviral therapy (post-ART) era. In countries with ready access to ART, approximately one-third of KS cases present in patients with undetectable HIV loads and CD4 counts of ≥200 cells/µl. This is in contrast to pre-ART era KS, which was associated with systemic HIV replication and CD4 counts of ≤200 cells/µl. Using primary patient biopsy specimens, we identified a novel molecular signature that characterizes AIDS KS lesions that develop in HIV-suppressed patients on ART: KSHV transcription is limited in HIV-suppressed patients. With one exception, only the canonical viral latency mRNAs were detectable. In contrast, early AIDS KS lesions expressed many more viral mRNAs, including, for instance, the viral G protein-coupled receptor (vGPCR).

Antimicrobial therapy for the treatment of opportunistic infections in HIV/AIDS patients: a critical appraisal

The widespread use of antiretroviral therapy (ART) has entirely changed the management of human immunodeficiency virus (HIV) infection and dramatically reduced the rates of opportunistic infections (OI). However, OI continue to cause significant morbidity and mortality in both developed countries, where presentation with advanced HIV infection is common, and also in developing countries where ART is less widely available. Evidence to direct OI guidelines is partly limited by the fact that many large-scale studies date from the pre-ART era and more recent studies are sometimes poorly powered due to the falling rates of OI. Treatment of OI is now known to be as much about antimicrobials as about immune reconstitution with ART, and recent studies help guide the timing of initiation of ART in different infections. OI have also become complicated by the immune reconstitution inflammatory syndrome phenomenon which may occur once successful immune recovery begins. Trimethoprim-sulfamethoxazole has long been one of the most important antibiotics in the treatment and prevention of OI and remains paramount. It has a broad spectrum of activity against Pneumocystis jiroveci, toxoplasmosis, and bacterial infections and has an important role to play in preventing life-threatening OI. New advances in treating OI are coming from a variety of quarters: in cytomegalovirus eye disease, the use of oral rather than intravenous drugs is changing the face of therapy; in cryptococcal meningitis, improved drug formulations and combination therapy is improving clearance rates and reducing drug toxicities; and in gut disease, the possibility of rapid immune restitution with ART is replacing the need for antimicrobials against cryptosporidia and microsporidia.

Quality care: a link between clinical and public health approaches to HIV infection in developing countries

As the importance of quality in health care provision is increasingly recognised, it is opportune to consider quality care as a key link between clinical and public health approaches to human immunodeficiency virus (HIV) infection in developing countries, especially in sub-Saharan Africa. This region has the lion's share of the global epidemic and the least resources to respond. Looking at health problems using a 'quality lens' may help bridge the gaps between clinical care and public health, the current and desired standard of care, and prevention and treatment. Quality care, with prompt diagnosis and effective treatment, of people with HIV infection is crucial for good individual health outcomes, public health outcomes (in terms of decreased HIV transmission) and societal outcomes (increased productivity and decreased costs of health provision for HIV-related care). A spotlight on quality care can bring clinicians and public health practitioners together in working towards universal access to quality HIV care and prevention - one of the greatest health challenges faced in developing countries in Africa today.

The ART of caring for patients with HIV infection in the ICU

The ART of caring for patients with HIV infection in the ICU

HIV morbidity and mortality in Jamaica: analysis of national surveillance data, 1993–2005

Pre-antiretroviral therapy (ART) HIV-related survival and timing of HIV identification have not been reported from the Caribbean. Using Jamaican national surveillance data, we estimated overall, AIDS-free, and AIDS survival, identified factors influencing HIV-related mortality, and examined factors associated with late HIV/AIDS identification. The Jamaican HIV/AIDS tracking system (HATS) national surveillance data included timing of first positive HIV test, stage at identification, date of AIDS diagnosis, and death. We estimated overall and AIDS-free survival by initial stage, using a proportional hazard model to identify factors associated with worse survival, and logistic regression to examine factors related to later case identification. Of 10674 reported HIV cases, 48% were asymptomatic, 14% symptomatic, and 38% first reported with AIDS. Five-year AIDS-free survival was 77% for asymptomatic persons and 63% for symptomatic. Median survival after AIDS diagnosis was 1.02 years. Age, number of opportunistic diseases, and initial stage were strongly associated with mortality. Older age, drug use, and sex with a commercial sex worker were associated with later identification. In the pre-ART era, over one-third of HIV-infected persons in Jamaica were first identified with advanced disease. This highlights the need for earlier diagnosis as ART programs roll out in the Caribbean.

Kaposi's sarcoma of the recto sigmoid colon in a patient with HIV infection and a high CD4 count

Kaposi's sarcoma (KS) is a well-recognized, HIV-associated opportunistic tumour, which was first described in 1872 by a Hungarian dermatologist, Moritz Kaposi. It predominantly affects homosexual men and heterosexual patients from Africa infected with HIV. The lesions can arise anywhere in the body but occur more frequently on the skin. Despite a trend towards lower CD4 counts at the time of KS presentation, the use of antiretroviral therapy has been associated with a reduction in mortality compared with the pre-ART era. Prior to the introduction of highly active antiretroviral therapy, 40% of people with KS skin lesions were reported to have lesions in the intestine. Conversely, KS can also develop systemically in the absence of skin lesions. We present a case of KS affecting the distal sigmoid colon and rectum in a patient with a relatively preserved CD4 T-cell count, demonstrating that a less common presentation of KS may occur at any CD4 count.

The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy

The pulmonary manifestations of HIV disease in 2005 can be divided into two sets of presentations. For patients who do not have access to care, and who are not taking antiretroviral or chemoprophylactic drugs, opportunistic infections and neoplasms continue to occur. Pulmonary disease caused by Streptococcus pneumoniae, Pneumocystis carinii (now known as Pneumocystis jiroveci pneumonia; PCP), Mycobacterium tuberculosis, lymphoma, and Kaposi’s sarcoma present much as they did in the 1980s. Management has improved in terms of new diagnostic, therapeutic, and preventive strategies, as reviewed in guidelines issued jointly by the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Disease Society of America (available online at http://www.aidsinfo.nih.gov).

Does Highly Active Antiretroviral Therapy Increase the Risk of Congenital Abnormalities in HIV-Infected Women?

Does Highly Active Antiretroviral Therapy Increase the Risk of Congenital Abnormalities in HIV-Infected Women?