The full benefit of many effective medications will be achieved only if patients adhere to prescribed treatment regimens. Unfortunately, applying terms such as “noncompliant” and “nonadherent” to patients who do not consume every pill at the desired time can stigmatize them in their future relationships with health care providers. This article on medication adherence (or compliance) reviews strategies to assess and enhance this important aspect of patient care.

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Adherence to Medication

Background In most subjects infected with human immunodeficiency virus type 1 (HIV-1), clinical or laboratory evidence of immunodeficiency develops within 10 years of seroconversion, but a few infected people remain healthy and immunologically normal for more than a decade. Studies of these subjects, termed long-term survivors, may yield important clues for the development of prophylactic and therapeutic interventions against the acquired immunodeficiency syndrome. Methods and Results We studied 10 seropositive subjects who remained asymptomatic with normal and stable CD4+ lymphocyte counts despite 12 to 15 years of HIV-1 infection. Plasma cultures were uniformly negative for infectious virus. However, particle-associated HIV-1 RNA was detected in four subjects with a sensitive branched-DNA signal-amplification assay, whereas in five others the levels of HIV-1 RNA were too low to detect. Infectious HIV-1 was detected in peripheral-blood mononuclear cells (PBMC) of three subjects by standard limiting-dilut...

https://www.nejm.org/doi/pdf/10.1056/NEJM199501263320401

Virologic and Immunologic Characterization of Long-Term Survivors of Human Immunodeficiency Virus Type 1 Infection

Mood disorders in the medically ill: scientific review and recommendations.

The use of peptide–human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8+ T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8+ T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, and perforin is analyzed by FACS® within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8+ T cells compared with cytomegalovirus (CMV)-specific CD8+ T cells in HIV chronic infection. We show that the majority of circulating CD8+ T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-γ and MIP-1β but not TNF-α. However, a striking finding is that HIV-specific CD8+ T cells express significantly lower levels of perforin than CMV-specific CD8+ T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8+ T cells are impaired in cytolytic activity.

/pdf/hiv-specific-cd8-t-cells-produce-antiviral-cytokines-but-are-4ukn9q7gfl.pdf

HIV-Specific Cd8+T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function

Pathogenesis of human immunodeficiency virus infection.

Two strategies to increase adherence to HIV antiretroviral medication: Life-Steps and medication monitoring

Life-steps: Applying cognitive behavioral therapy to HIV medication adherence

The CNS is a common target for human immunode-ficiency virus (HIV) infection. [1-3] In pathologic studies conducted before the use of zidovudine (AZT), CNS changes were found to be related to HIV in nearly two-thirds of acquired immunodeficiency syndrome (AIDS) patients; in more recent studies it is estimated that 20 to 30% of these patients will develop dementia. [1,2,4] This disorder, called the AIDS dementia complex (ADC), is entirely separate from the secondary opportunistic infections and tumors that also occur in the brains of HIV-infected patients. [1,2,5]

Pathologic lesions in ADC are predominantly localized to white and deep gray matter structures and typically include pallor of the white matter, gliosis, and perivascular and parenchymal infiltrates of macrophages, lymphocytes, and multinucleated giant cells. [1,2,6,7] By using quantitative morphometry, several groups found a 30 to 50% loss of large neurons in the cortical regions of patients with HIV encephalitis [6,8] and in brains with minimal pathology. [9,10] Confocal laser imaging and golgi impregnation studies also identified abnormalities of the dendritic tree, including a 40% loss of the dendritic area and 40 to 60% loss of spine density compared with controls. [11] The relationship of these findings to the severity of dementia remains poorly understood, however. Although HIV is thought to be the causative agent of ADC, neurons and glial cells are not commonly infected, [12-14] suggesting that brain injury may be related to indirect mechanisms. [15,16]

N-acetyl aspartate (NAA), a metabolite exclusively found in neurons [17,18] and commonly used as a neuronal marker, can be detected by proton magnetic resonance spectroscopy (1) H-MRS) noninvasively.1 H-MRS also measures total creatine (as a sum of phosphocreatine and creatine) and choline-containing compounds (i.e., those containing the [CH3]3 Nplus- group). Thus,1 H-MRS provides a noninvasive way to follow changes in …

Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex A proton magnetic resonance spectroscopic study

Human immunodeficiency virus type 1 (HIV-1) infection is associated with elevated levels of inflammatory cytokines in the serum and cerebrospinal fluid of infected persons, but the sources of these proteins as well as the specific stimuli which trigger their production and release have not been fully defined. In this study, we evaluated the ability of HIV-1-specific cytotoxic T-lymphocyte (CTL) clones derived from seropositive persons to release gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and TNF-beta upon contact with target cells presenting viral antigen. Peripheral blood- and cerebrospinal fluid-derived HIV-1-specific CD3+ CD4- CD8+ CTL clones as well as freshly isolated peripheral blood mononuclear cells from infected persons were tested in parallel for HIV-1-specific cytotoxicity and cytokine release. Target cells consisted of autologous and allogeneic B-lymphoblastoid cell lines sensitized with synthetic HIV-1 peptides containing the epitopes recognized by these CTL. Cytokine production was measured by specific enzyme-linked immunosorbent assay of culture supernatant fluid. HIV-1-specific CTL clones directed at envelope, Gag, reverse transcriptase, and Nef epitopes specifically released IFN-gamma, TNF-alpha, and TNF-beta upon contact with their relevant target epitopes but not following contact with irrelevant epitopes. These cytokines were released in an HLA class I-restricted fashion, and release was detectable as early as 4 to 6 h of incubation and remained elevated at 48 h. Fresh peripheral blood mononuclear cells from a seropositive person likewise released IFN-gamma in an antigen-specific and HLA class I-restricted manner when incubated with target cells presenting a peptide containing a CTL epitope, paralleling the HIV-specific cytolytic activity of these cells. These studies indicate that in addition to mediating direct cytotoxicity, HIV-1-specific CTL may affect other immune responses by releasing IFN-gamma, TNF-alpha, and TNF-beta. Elevated levels of these cytokines which have been detected in serum and cerebrospinal fluid of infected persons may be due at least in part to the persistent HIV-1-specific CTL response.

Human immunodeficiency virus type 1-specific cytotoxic T lymphocytes release gamma interferon, tumor necrosis factor alpha (TNF-alpha), and TNF-beta when they encounter their target antigens.

AIDS dementia complex is a common neurologic disorder in later stages of HIV-1 infection. Because virus-specific CTL have been shown to contribute to neurologic disease in certain viral illnesses, we examined the cerebrospinal fluid of HIV-1-infected persons with various stages of AIDS dementia complex for the presence of HIV-1-specific CTL. In five of six subjects studied, HIV-1-specific CTL were identified in the cerebrospinal fluid. These CTL were directed at epitopes within the gag, reverse transcriptase, envelope, and nef proteins and restricted by HLA class I Ag. In four of these subjects, virus-specific CTL were detected in higher numbers in the cerebrospinal fluid compared to the peripheral blood, suggesting a specific recruitment to or local induction within the nervous system. These studies demonstrate the presence of a vigorous and broadly directed CTL response to HIV-1 in the central nervous system of infected persons with AIDS dementia complex, and provide immunologic evidence of localized intrathecal infection. Although HIV-1-specific CTL may serve to inhibit viral replication in the central nervous system, the presence of a persistent CTL response in the central nervous system may also contribute to the neurologic disorders characteristic of HIV-1 infection.

Jonathan L. Worth

Papers

Two strategies to increase adherence to HIV antiretroviral medication: Life-Steps and medication monitoring

Life-steps: Applying cognitive behavioral therapy to HIV medication adherence

Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex A proton magnetic resonance spectroscopic study

Human immunodeficiency virus type 1-specific cytotoxic T lymphocytes release gamma interferon, tumor necrosis factor alpha (TNF-alpha), and TNF-beta when they encounter their target antigens.

Detection of a vigorous HIV-1-specific cytotoxic T lymphocyte response in cerebrospinal fluid from infected persons with AIDS dementia complex.