Stephen Kravcik

Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease

Summary Background Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. We undertook an international, multicentre, randomised, double-blind, placebo-controlled trial of ritonavir in patients with HIV-1 infection and CD4-lymphocyte counts of 100 cells/u, L or less, who had previously been treated with antiretroviral drugs. Methods 1090 patients were randomly assigned twice-daily liquid oral ritonavir 600 mg (n=543) or placebo (n=547) while continuing treatment with up to two licensed nucleoside agents. The primary study outcome was any first new, or specified recurrent, AIDS-defining event or death. Open-label ritonavir was provided after 16 weeks in the study to any patient who had an AIDS-defining event. Findings The baseline median CD4-lymphocyte count was 18 (IQR 10-43)/μ in the ritonavir group and 22 (10-47) /μL in the placebo group. Study medication was discontinued in 114 (21·1%) ritonavir-group patients and 45 (8·3%) placebo-group patients mainly because of initial adverse symptoms. Outcomes of AIDS-defining illness or death occurred in 119 (21·9%) ritonavir-group patients and 205 (37·5%) placebo-group patients (hazard ratio 0·53 [95% Cl 0·42-0·66]; log-rank p Interpretation Although earlier intervention with combination therapy may provide much more effective treatment, ritonavir in patients with advanced disease and extensive previous antiretroviral use is safe and effective, lowers the risk of AIDS complications, and prolongs survival.

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection.

T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P<0.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBLs from HIV negative patients, and apoptosis sensitive PBLs from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

Development of Cervical Fat Pads Following Therapy with Human Immunodeficiency Virus Type 1 Protease Inhibitors

Eight patients with infection due to human immunodeficiency virus type 1 developed fat pads at the bases of their necks a median of 22 weeks (range, 4-61 weeks) after initiation of protease inhibitor therapy. This finding was seen in association with the use of each of the available protease inhibitors. The patients had no other cushingoid features or histories of corticosteroid use, and all had normal 24-hour urine cortisol levels. The computed tomography scans of five patients showed large, nonencapsulated accumulations of subcutaneous adipose tissue. Histological examination of tissue from one patient confirmed a nonlipomatous subcutaneous fat deposition. Although the pathogenesis of this unique clinical finding is unclear, the temporal relationship between the use of protease inhibitors and the development of cervical fat pads is suggestive of a complication of therapy.

Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10.

Objectives Natural killer (NK) cell function is likely to be important in controlling HIV infection and opportunistic pathogens. We therefore evaluated NK function and phenotype over the course of antiretroviral therapy (ART) and examined the potential mechanisms of altered NK activity in HIV infection. Methods We measured NK cell percentage, NK cytolytic activity (both by flow cytometry) and plasma IL-10 concentrations (by enzyme-linked immunosorbent assay) in 10 HIV-seropositive patients before and over one year of effective ART. To examine potential mechanisms of altered NK activity, we measured NK receptor expression in ART treated and untreated HIV-positive individuals by flow cytometry. As IL-10 enhances NK activity, we studied the effect of IL-10 on NK receptor expression and activity in peripheral blood mononuclear cells (PBMC) from HIV-seronegative individuals. Results NK cytolytic activity was elevated in HIV infection and decreased with ART to levels observed in HIV-negative individuals. A greater proportion of NK cells from untreated HIV-positive individuals expressed the NK receptors CD158a and CD161 than either HIV-negative volunteers or effectively treated HIV-positive patients. NK cells from PBMC incubated with IL-10 demonstrated increases in CD158a, CD161 and CD94 expression and increases in cytolytic activity. The treatment-associated decrease in NK activity paralleled a decrease in IL-10 production. Conclusion The observation that IL-10 alters NK receptor expression similar to that observed in HIV infection, and the fact that NK receptor expression and activity normalize in parallel with ART-induced reduction of circulating IL-10 levels supports a role for IL-10 in NK cell activity and HIV immunopathogenesis.

Progressive Human Immunodeficiency Virus—Specific Immune Recovery with Prolonged Viral Suppression

The degree of immune recovery achievable with anti-human immunodeficiency virus (HIV) therapy remains to be established. The effects of potent antiretroviral therapy, including ritonavir and saquinavir, on immune function were studied for a prolonged period in 41 patients. After 96 weeks, 88% of patients had plasma HIV RNA levels below the limit of quantitation. There were continuous increases in CD4 lymphocyte counts and in CD4:CD8 ratios over time. About half the patients developed lymphoproliferative responses to HIV p24 antigen, and nearly all developed responses to phytohemagglutinin. This occurred in parallel with increases in interleukin-12 production and expression of CD28 on CD8 lymphocytes, despite potential antiproliferative effects of protease inhibitors. Transient increases in virus load were temporally associated with loss of proliferative responses. The improved immune function, including HIV-specific immunity in many subjects, demonstrates the potential reversibility of HIV-induced immunodeficiency and does not identify a limit to immune recovery.

Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T-cell count < 200 cells/??l when viral replication is suppressed

Objective:To determine the safety of discontinuing Pneumocystis jiroveci pneumonia (PCP) prophylaxis, in patients on effective antiretroviral therapy with CD4+ T-cell counts that have plateaued at < 200 cells/μl. Methods:We prospectively evaluated a cohort of HIV infected patients at a multidisciplinary HIV clinic with sustained HIV RNA levels < 50 copies/ml and CD4+ T-cell counts that have plateaued at < 200 cells/μl and who have discontinued PCP prophylaxis. Results:Nineteen patients fulfilled the above criteria. Eleven had been taking daily trimethoprim–sulfamethoxazole, seven were receiving monthly aerosolized pentamidine, and one patient never received any prophylaxis. The median CD4+ T-cell count at the time of discontinuation and at the most recent determination were 120 (range, 34–184) and 138 (range, 6–201) cells/μl, respectively. To date, patients have been off PCP prophylaxis for a mean of 13.7 ± 10.6 months and a median of 9.0 (range 3–39) months for a total of 261 patient-months. To date, no patient has developed PCP. This is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/μl in untreated HIV infection (rate difference 9.2%; 95% confidence interval, 5.7 to 12.8%; P < 0.05). Conclusion:With sustained suppression of viral replication, PCP prophylaxis may not be necessary, regardless of CD4+ T-cell count. This illustrates a degree of immune recovery that occurs with virologic suppression that is not reflected in absolute CD4+ T-cell count or percentage and suggests that guidelines for P. jiroveci pneumonia prophylaxis may need to be re-evaluated.

Comparative CD4 T-Cell Responses of Reverse Transcriptase Inhibitor Therapy With or Without Nelfinavir Matched for Viral Exposure

Abstract Background: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). Purpose: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. Results: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p < .05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. Conclusion: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

HIV lipodystrophy: a review.

Abstract The dramatic clinical benefit of highly active antiretroviral therapy has been offset, to an extent, by the development of unforeseen long-term toxicities. Of these, the HIV lipodystrophy syndrome is most prominent. The array of related but possibly separate manifestations includes fat deposition and atrophy and metabolic complications such as hyperlipidemias and diabetes mellitus. These have been attributed to the use of protease inhibitors, but other factors may be involved, particularly the use of nucleoside reverse transcriptase inhibitors, especially stavudine. The pathogenesis of any of the manifestations of the syndrome remains to be explained. The metabolic complications may respond to standard treatments, but most therapies directed at fat changes have been unsuccessful. This review will summarize the state of knowledge in the field.

Update on HIV Lipodystrophy

Abstract When prescribed appropriately and taken adherently, antiretroviral therapy can consistently and durably suppress HIV replication, potentially translating into years of near normal health for HIV-infected persons. However, presently available antiretrovirals are associated with a cluster of physical and metabolic symptoms termed HIV lipodystrophy. This article reviews the state of knowledge about the pathogenesis and treatment of the various manifestations of these adverse effects.

An HIV-Positive Patient with Back Pain: Too Many Choices

A 57-year-old, human immunodeficiency virus (HIV)infected male presented with a 2-month history of progressive lower back discomfort accompanied by left leg weakness and right thigh and calf cramping. He was not on HIV antiretroviral (ARV) therapy; his most recent CD4 count was 169 cells/μL (normal range, 628– 1698) and his viral load (VL) was 146,207 copies/mL. This man’s low back pain with lower extremity weakness and cramping most importantly suggests the possibility of cauda equina syndrome or spinal root compression. For the sake of completeness, I would like to know whether he has any bowel or bladder symptoms, or any sensory symptoms. As well, I would like to know whether his weakness is progressive, and whether there are aggravating or alleviating factors. If the pain is slowly progressive, the differential diagnosis is quite broad, and neoplastic disease of the spinal cord and extrinsic compression by epidural or intradural tumor may present in this manner. Demyelinating, degenerative and metabolic or deficiency disease may present in this way as well. Here, an initial problem presentation is construed. The clinician is formulating a hypothesis that could account for this man’s presentation. By eliciting further elements of the patient’s history, the clinician is assembling information that will either uphold or discredit this hypothesis. The clinician is attempting to determine whether this man has any symptoms suggestive of cauda equina syndrome, which is a medical emergency requiring urgent surgical intervention. The list of etiologies causing spinal root compression or other spinal cord processes is quite extensive, although the chronicity of the presentation will help narrow the list. The back discomfort and leg weakness came on gradually. There was no past history of back symptoms or injury. He denied any bowel incontinence, although he had been constipated for a few weeks. Over the 1 to 2 weeks following his initial presentation, he developed urinary urgency and urge incontinence, but denied any sexual difficulties, postural headache or dizziness. Apart from the back pain, he denied any history of numbness, tingling or paresthesias in his limbs. Similarly, there was no history of any numbness or sensory loss in his sacral area. In any middle-aged male regardless of HIV seropositivity, spinal cord compression from malignancy, infection or intervertebral disk herniation must be considered. Malignancies common in a male over 50, regardless of HIV serostatus, include metastatic disease from prostate cancer, lung cancer and colon cancer, as well as multiple myeloma. Lung and colon cancer may also be associated with paraneoplastic disorders that can, in turn, affect the spinal cord. I would ask about the presence of B symptoms, smoking, dyspnea and change in bowel habits. Other infections that are not necessarily HIV-associated, such as bacterial abscess secondary to seeding from bacteremia, or herpes simplex virus (HSV), can also present with spinal cord symptoms. These may occur in both immunocompetent and immunocompromised hosts. Other infections, such as Toxoplasmosis and JC virus, can also cause myelitis, but are most often seen in immunosuppressed hosts. Tuberculous infection of the spine with secondary cord compression is a possibility, so I would ask about risk factors for, and symptoms of, tuberculosis. HIV-infected individuals are more likely to have virtually all the infections that would present with spinal root compression symptoms. Here the clinician continues to gather further historical information in order to prioritize his differential diagnoses. Received June 16, 2013 Revised September 5, 2013 Accepted December 5, 2013 Published online January 7, 2014 JGIMIn this series, a clinician extemporaneously discusses the diagnostic approach (regular text) to sequentially presented clinical information (bold). Additional commentary on the diagnostic reasoning process (italics) is integrated throughout the discussion.