Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Osteonecrosis in patients infected with human immunodeficiency virus: a case-control study.

To evaluate risk factors for osteonecrosis in human immunodeficiency virus (HIV)-infected patients, demographic and clinical characteristics of case patients (n=17) and control patients (n=34) matched on initial clinic visit date, length of follow-up, and baseline CD4 cell count were compared. Case patients were more likely to have received corticosteroids (47.1% vs. 8.8%; matched odds ratio [OR], 13.1; 95% confidence interval [CI], 1.6-106), to have had an increase in CD4 cell count from nadir >0.050 x 10(9) cells/L (64.7% vs. 35.3%; OR, 4.9; 95% CI, 1.0-24), and to have had Pneumocystis carinii pneumonia (52.9% vs. 11.8%; OR, 7.6; 95% CI, 1.6-36). Use of protease inhibitors and history of other opportunistic infections did not significantly differ. In multivariate analysis, use of corticosteroids remained significantly associated with osteonecrosis, independently of HIV disease stage and protease inhibitor therapy. Corticosteroid use is an important risk factor for osteonecrosis, but its pathogenesis is likely multifactorial.

Coronary artery disease and human immunodeficiency virus infection.

Recent reports of myocardial infarctions in young persons infected with human immunodeficiency virus (HIV) who are receiving protease inhibitor therapy have raised concerns about premature coronary artery disease in this population. Endothelial dysfunction, hypercoagulability, hypertriglyceridemia, and abnormal coronary artery pathology were in fact associated with HIV infection prior to the availability of protease inhibitor therapy. Newly recognized risk factors, such as insulin resistance, hypercholesterolemia, and fat redistribution syndrome, may exacerbate underlying atherosclerotic risk for patients receiving protease inhibitors. Data on the incidence of myocardial infarction among these patients are largely limited to case reports but are of concern. Pending the availability of further data, it is prudent to monitor these patients for hyperlipidemia and consider interventions to modify cardiac risk factors.

Interpreting HIV clinical trials.

AIDS: The complexities of design and analysis of HIV clinical trials are important factors to consider when interpreting a study. Common design concepts such as blinding and randomization are described. A table illustrates how the effects of different analyses of the same data can lead to differing interpretations of the results. Intent-to-treat analysis is presented as a more rigorous approach that is representative of clinical practice.^ieng

Finding the truth: a guide to interpreting HIV clinical trials.

The complex social, epidemiologic, and pathologic aspects of HIV disease, the variation in the nature of the disease from person to person, and the constantly changing roster of available treatments create intense and often contradictory concerns. Clinical trials are rarely interested only in the study patients, but are designed to enable us to make inferences about a general HIV-infected population. To do this most effectively, we must confirm the internal and external validity of the study. Statistics enable us to generalize from a particular study to the broader population, but the statistical problems arising from AIDS clinical trials are unique and complex.

Immunizations during HIV infection.

The safety and efficacy of immunizing HIV-infected persons for other diseases has been controversial. Transient increases in HIV viral load have been reported in some but not all studies of immunization, and are unlikely to have adverse clinical consequences, particularly in the era of more active antiretroviral therapy. Although the serological response to immunization is reduced in the HIV-infected host, recent data suggest that it has some clinical efficacy.

The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double-blind, placebo-controlled study.

To determine if vaccination induces replication of human immunodeficiency virus type 1 (HIV-1), 42 HIV-1-infected subjects with CD4 cell counts of 200-500 cells/microL were randomized to receive influenza vaccine or saline placebo. Infectious cell-associated and plasma HIV-1 RNA virus load were measured twice at baseline and then at 7, 10, 14, and 30 days after injection by quantitative microculture and branched DNA amplification. The ratios of the geometric mean plasma HIV-1 load of the four follow-up visits compared with baseline in vaccine (n = 28) and placebo (n = 14) recipients were similar (1.05 [95% confidence interval, 0.80-1.37] for vaccine; 0.96 [95% confidence interval, 0.68-1.33] for placebo; P = .90). The geometric mean ratios of plasma virus load at each follow-up visit to baseline did not differ significantly from 1.0 for each group. Infectious cell-associated virus load measures yielded similar results. CD4 cell counts declined similarly in both groups at 6 months. Influenza vaccination did not increase HIV-1 load in this controlled clinical trial.

Use of antiherpes drugs and the risk of Kaposi's sarcoma: data from the Multicenter AIDS Cohort Study.

To determine if use of antiherpes drugs protects against the development of AIDS-associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis, neither acyclovir use for human immunodeficiency virus infection (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.56-1.26; P = .39) nor acyclovir use for any indication (OR, 1.02; 95% CI, 0.76-1.38; P = .89) was associated with a reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir was also not protective against developing KS as a late manifestation of AIDS (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease, ganciclovir use (relative risk [RR], 0.56; 95% CI, 0.22-1.44; P = .23) and foscarnet use (RR, 0.40; 95% CI, 0.051-3.10; P = .38) were associated (although not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear to reduce the risk of KS, but further study of other antiherpes drugs such as ganciclovir and foscarnet is warranted.

Survivor treatment selection bias in observational studies: examples from the AIDS literature.

Unlike patients in a randomized, clinical trial, patients in an observational study choose if and when to begin treatment. Patients who live longer have more opportunities to select treatment; those who die earlier may be untreated by default. These facts are the essence of an often overlooked bias, termed "survivor treatment selection bias," which can erroneously lead to the conclusion that an ineffective treatment prolongs survival. Unfortunately, misanalysis of survivor treatment selection bias has been prevalent in the recent literature on the acquired immunodeficiency syndrome. Approaches to mitigating this bias involve complex statistical models. At a minimum, initiation of therapy should be treated as a time-dependent covariate in a proportional hazards model. Investigators and readers should be on the alert for survivor treatment selection bias and should be cautious when interpreting the results of observational treatment studies.

Tuberculin skin test reactivity, anergy, and HIV infection in hospitalized patients. Longcope Firm of the Osler Medical Housestaff.

PURPOSE: Detection of latent tuberculosis infection is an important step in the control of tuberculosis because high-risk persons may be given preventive therapy. The value of tuberculin skin testing in individuals with human immunodeficiency virus (HIV) infection, however, is limited by anergy. We evaluated the prevalence of tuberculin skin test reactivity, anergy, and HIV infection in a group of hospitalized patients in an area where both tuberculosis and HIV infection are prevalent. PATIENTS AND METHODS: Three hundred fifty-one patients consecutively admitted to a medical service of a large urban teaching hospital were enrolled in the study. All those with no documented history of a positive tuberculin skin test were evaluated on admission with purified protein derivative (PPD) by the Mantoux test, and with anergy testing using a multiple-puncture device. HIV testing was offered to all patients who did not have a known history of HIV infection, and was performed when informed consent was obtained. RESULTS: Forty-one patients (12%) had a documented history of a positive PPD. Of the remaining 310 patients, 62 (20%) had a PPD response of > or = 10 mm induration. Fifty-two (15%) of the 351 patients were HIV positive. None of the HIV-infected patients was PPD positive. Anergy was found in 63% of the HIV-infected patients and 28% of the HIV-seronegative patients. Independent risk factors for a positive PPD included age > 55, male sex, and hypertension. HIV infection, current steroid use, and a history of cancer were associated with a negative PPD. Independent risk factors for anergy included HIV infection, current corticosteroid use, renal failure pneumonia, and a history of cancer. Of the 62 new PPD-positive patients, 30 (48%) were candidates for chemoprophylaxis. Additionally, 30 (63%) of 48 HIV-seropositive patients who were completed testing were anergic and might be candidates for chemoprophylaxis. Almost all of the patients eligible for chemoprophylactic therapy would have been detected if only patients at increased risk for developing tuberculosis were screened. CONCLUSIONS: Tuberculosis infection, HIV infection, and anergy were common in patients admitted to this medical service. Interpretation of PPD reactivity was confounded by a high prevalence of anergy, particularly in HIV-infected patients. A large proportion of patients tested were candidates for chemoprophylaxis. Routine tuberculin skin testing with anergy testing for high-risk patients on admission to the hospital is useful for identifying patients who might benefit from prophylaxis to help control the spread of tuberculosis.

Lumbar puncture for evaluation of latent syphilis in hospitalized patients. High prevalence of cerebrospinal fluid abnormalities unrelated to syphilis.

OBJECTIVE: To determine the prevalence of abnormal neurologic findings and cerebrospinal fluid abnormalities in hospitalized patients with serologic evidence of latent syphilis. DESIGN: Cross-sectional survey. METHODS: Consecutively admitted hospital inpatients from an inner-city population were screened for serologic evidence of syphilis with reactive plasma reagin and confirmatory fluorescent treponemal antibody absorption assays. In those with reactive tests, such clinical findings as a history of treatment for syphilis, neurologic abnormalities, presence of human immunodeficiency virus infection, and rapid plasma reagin titer were correlated with cerebrospinal fluid white blood cell count, protein level, and VDRL result. RESULTS: Of 490 consecutive patients, 52 (11%) had serologic evidence of syphilis. Forty-three (83%) of these underwent lumbar puncture. Of the 43, 31 (72%) were seronegative for human immunodeficiency virus and 12 (28%) were seropositive. No patient had a reactive cerebrospinal fluid VDRL test. Cerebrospinal fluid abnormalities were seen in 32% of human immunodeficiency virus-seronegative patients and in 67% of human immunodeficiency virus-seropositive patients. Cerebrospinal fluid abnormalities were not predicted by history of treatment for syphilis, abnormal neurologic findings, or an elevated rapid plasma reagin titer. Cerebrospinal fluid IgG indexes in patients with elevated cerebrospinal fluid protein levels suggested that the protein abnormalities were not caused by local antibody production. Nonreactive cerebrospinal fluid fluorescent treponemal antibody absorption tests suggest that the cerebrospinal fluid abnormalities were not the result of neurosyphilis. CONCLUSIONS: There was a high prevalence of cerebrospinal fluid abnormalities in hospitalized patients with latent syphilis detected by routine screening. Because of the nonspecificity of the cerebrospinal fluid findings, routine lumbar puncture for such patients appears to contribute little to the treatment of latent syphilis.

Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus.

To determine the incidence and clinical manifestations of herpes zoster in a hospital-based clinic for adults infected with human immunodeficiency virus (HIV), we reviewed the records of all patients for whom zoster was diagnosed at or after their first clinic visit. Fifty-two episodes of zoster occurred in 45 patients during 1,614 person-years of follow-up (incidence, 3.2 episodes per 100 person-years). The following major complications of zoster occurred in 12 patients (27%): ocular complications (5), neurological complications (4), and chronic atypical skin lesions (5). Six patients each had postherpetic neuralgia and bacterial superinfection, which were the common minor complications of zoster. Multivariate analysis revealed that only a low CD4 cell count (< or = 200/mm3) was predictive of a major complication of zoster (OR, 13.2; 95% CI, 1.52-114; P = .019). Thus, complications of herpes zoster are common in patients with HIV infection, especially those with advanced immunosuppression.

Herpes zoster in patients with advanced human immunodeficiency virus infection treated with zidovudine. Zidovudine Epidemiology Study Group.

To determine the prevalence, incidence, and effects on disease progression and survival of herpes zoster in patients with advanced human immunodeficiency virus (HIV) disease, data from a multicenter observational cohort study of 1044 patients with AIDS or AIDS-related complex (ARC) and CD4 cell count < or = 0.25 x 10(9)/L treated with zidovudine were analyzed. Of 163 patients (16%) with a history of herpes zoster at enrollment, 22 (13%) had a recurrence during the 2-year follow-up. For those without prior herpes zoster, the probability of its development was 6.3% at 1 and 8.8% at 2 years. Progression to AIDS was not associated with herpes zoster. By proportional hazards analysis, an initial occurrence of herpes zoster was associated with prolonged survival independent of baseline CD4 cell count and disease stage; however, recurrence tended to be associated with death. Thus, herpes zoster is relatively common in advanced HIV infection and its initial occurrence late in disease may indicate improved prognosis.

Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum.

More than half of all patients evaluated in our clinic for the possible diagnosis of a heritable disorder of connective tissue could not be classified in the current nosology, yet they had considerable clinical evidence of a systemic defect of the extracellular matrix. As a group, these patients share many manifestations of the Marfan syndrome including long limbs, deformity of the thoracic cage, striae atrophicae, mitral valve prolapse, and mild dilatation of the aortic root. Clinical clustering did not emerge when patients were stratified by mitral valve prolapse or aortic dilatation. The clinical phenotype of patients with mitral valve prolapse constitutes a continuum, from Marfan syndrome at one extreme to isolated mitral valve prolapse due to myxomatous proliferation of the valve leaflets. In the absence of biochemical or DNA markers, discerning whether a patient with mitral valve prolapse and mild aortic root dilatation (in the absence of ectopia lentis or a family history) has Marfan syndrome, or another heritable disorder of connective tissue, will continue to be a clinical challenge. Until subclassification based on refined clinical, genetic, and laboratory investigations is possible, the patients we describe are best seen as having an "overlap" heritable connective-tissue disorder. We suggest the acronym "MASS phenotype" to emphasize involvement of the mitral valve, aorta, skeleton, and skin.

Serum CK, calcium, magnesium, and oxidative phosphorylation in mdx mouse muscular dystrophy.

Serum creatine kinase (CK) activity, calcium (Ca) and magnesium (Mg) contents of skeletal muscle and isolated mitochondria, as well as oxidative phosphorylation of X-linked muscular dystrophic (mdx) mice were compared with normal control animals at ages 5, 10, and 23 weeks. Serum CK is elevated in mdx mice at all ages, with highest activities at 5 weeks. The Ca content of dystrophic skeletal muscle is increased at all ages, whereas no clearly abnormal trend in muscle Mg levels was observed. Noncollagen protein (NCP), which was used as a reference base, is significantly diminished in muscle from 10- and 23-week-old mdx animals. Isolated mitochondria from mdx mice have elevated calcium content and decreased respiratory control ratios with NAD-linked substrates pyruvate/malate. The findings are distinct from those in dystrophic mice, strain 129/ReJ, but similar to observations in dystrophic hamsters and Duchenne muscular dystrophy and reflect the occurrence of overt muscle cell necrosis.