A simple self-reported adherence tool as a predictor of viral rebound in people with viral suppression on antiretroviral therapy.

OBJECTIVES: The aim of the study was to investigate the relationship between self-reported antiretroviral therapy (ART) adherence and virological outcomes in the multinational Strategies for Management of Antiretroviral Therapy (SMART) study. METHODS: Eligible participants were from the continuous ART arm and had at least one viral load (VL) ≤ 50 HIV-1 RNA copies/mL and a subsequent VL value (VL pair). Self-reported adherence was measured at each visit using a five-point Likert scale which employed a 7-day recall. High adherence was defined as taking 'all pills every day' (level 1) for every regimen component; all others had suboptimal adherence (levels 2 - 5). In individuals with VL suppression (≤ 50 copies/mL), the association between adherence (at the time of VL suppression) and VL rebound (> 200 copies/mL at next visit) was assessed using multivariable logistic regression with generalized estimating equations. RESULTS: A total of 10 761 sets of VL pairs from 1986 participants were included in the study. For 1220 (11%) VL pairs, adherence was suboptimal. For 507 VL pairs (5%), VL rebound occurred. The risk of rebound generally increased as adherence decreased: 4.2% for level 1, 7.7% for level 2, 16.3% for level 3, 9.4% for level 4 and 12.9% for level 5. In multivariable analysis, suboptimal adherence at the time of suppression was associated with a 50% increased odds of experiencing subsequent VL rebound [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.19-1.92; P = 0.0023], compared with high adherence. CONCLUSIONS: Self-reported suboptimal adherence in people with VL suppression is associated with an increased risk of VL rebound. Our findings highlight the importance of continued adherence counselling, even in people with VL suppression, and to ensure that people with HIV infection maintain excellent adherence in order to minimize the risk of VL rebound.

Recurrent pneumococcal bacteremia: risk factors and outcomes.

BACKGROUND: Recurrent pneumococcal bacteremia receives infrequent mention in the literature, usually in association with patients who are immunocompromised. OBJECTIVE: To examine recurrent cases of pneumococcal bacteremia to determine risk factors and outcomes (mortality rates and emergence of resistance) associated with recurrences. METHODS: We retrospectively reviewed all cases of pneumococcal bacteremia identified by our microbiology laboratory from January 1, 1992, through December 31, 1996. Demographic, clinical, and laboratory data were abstracted. RESULTS: There were 462 bacteremic episodes in 432 patients; 23 of these patients had 30 recurrent episodes. The 5.3% recurrence rate (23/432) is greater than that previously described. The median time to recurrence was 200 days. The mean age of patients with recurrences was 34 years, 70% were women, all were black or Hispanic (in near equal numbers), and 87% were infected with the human immunodeficiency virus (HIV). Human immunodeficiency virus infection, coexistent cancer, and female sex were independent predictors of recurrence. Only patients who were HIV-infected had multiple recurrences. Isolates from recurrent bacteremias were more likely to be penicillin-resistant than were initial bacteremic isolates (relative risk, 2.0; P =.16). Patients with recurrences had a higher (although not statistically significant) mortality rate than those without recurrences (22% vs 16%; P =.33). There was an inverse relationship between severity of illness and likelihood of recurrence. CONCLUSIONS: Rates of recurrent pneumococcal bacteremia may be higher than previously reported. In patients with recurrent pneumococcal bacteremia, the presence of an underlying immunodeficiency should be investigated.

Fever among outpatients with advanced human immunodeficiency virus infection.

BACKGROUND: Fever is common among persons with human immunodeficiency virus (HIV) infection. However, the clinical implications of fever in this population have not been evaluated. We therefore undertook a prospective study of fever in persons with advanced HIV infection to determine the incidence and etiology of fever in this patient group. METHODS: Prospective natural history study of 176 patients with advanced HIV infection followed up at Memorial Sloan-Kettering Cancer Center, New York, NY, from April 1, 1990, through December 31, 1990. RESULTS: Fever occurred in 46% of patients. A diagnosis was made in 83% of episodes, with acquired immunodeficiency virus-defining illnesses accounting for half of the diagnosed cases. Patients whose conditions required more than 2 weeks to diagnose most often had lymphoma, Mycobacterium avium-intracellulare bacteremia, or Pneumocystis carinii pneumonia. Four patients had persistent unexplained fever without a clear source. Only one patient had fever that clearly responded to antiretroviral therapy. CONCLUSIONS: Fever is common among outpatients with advanced HIV infection. Human immunodeficiency virus itself is rarely the cause of fever in such patients; the cause of the fever should be thoroughly evaluated.

Syphilis treatment response in HIV-infected individuals.

The adequacy of treatment for syphilis has routinely been evaluated by the serological response, i.e. the rapid plasma reagin test (RPR). Since the description of AIDS and HIV aspects of both the natural history of syphilis and the response of Treponema pallidum to treatment have come under increased scrutiny. With concurrent epidemics of HIV and syphilis in New York City, a serological case-control study was done to determine whether HIV-infected individuals given treatment for primary or secondary syphilis have a modified serological response. All study participants had primary or secondary syphilis and paired specimens available for testing. Cases were defined as people who were HIV-positive and were compared with controls who were HIV-negative. HIV-infected patients with primary syphilis when compared with HIV-negative controls were less likely to have a fourfold or greater RPR decrease or seroreversion within 6 months of treatment [15 out of 28 versus 153 out of 210; odds ratio = 0.4, P less than 0.05]. Cases and controls with secondary syphilis had similar serological responses after treatment for syphilis. Although this study adds to the growing body of literature which suggests that HIV may alter the RPR response, prospective studies are needed to determine definitively whether HIV alters the serological response to therapy in patients with early syphilis.

Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack).

A study of risk factors for HIV-1 infection was conducted at a sexually transmitted disease clinic in an area of New York City where the cumulative incidence of AIDS in adults through mid-1990 was 9.1 per 1000 of the population and where the use of illicit drugs, including smokable freebase cocaine (crack), is common. The overall seroprevalence among volunteers was 12% (369 out of 3084), with 80% of those who were seropositive reporting risk behavior associated with HIV-1 infection, including male-to-male sexual contact, intravenous drug use and heterosexual contact with an intravenous drug user. The seroprevalence in individuals denying these risks was 3.6% (50 out of 1389) and 4.2% (22 out of 522) in men and women, respectively. Among these individuals, the behaviors significantly associated with infection were use of crack and prostitution in women, and history of syphilis and crack use in men. These results suggest that in areas where the level of HIV-1 infection in heterosexual intravenous drug users is high and the use of crack is common, increased sexual activity (including the exchange of drugs or money for sex) may result in increased heterosexual transmission of HIV-1.

Susceptibility to levofloxacin of Myocobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. Community Programs for Clinical Research on AIDS 019 and the AIDS Clinical Trials Group 222 Protocol Team.

OBJECTIVE: To characterize the susceptibility to levofloxacin of clinical isolates of Mycobacterium tuberculosis (MTB) obtained from patients with HIV-related tuberculosis and to characterize the molecular genetics of levofloxacin resistance. DESIGN AND METHODS: Isolates from culture-positive patients in a United States multicenter trial of HIV-related TB were tested for susceptibility to levofloxacin by minimum inhibitory concentration (MIC) determinations in Bactec 7H12 broth. Automated sequencing of the resistance determining region of gyrA was performed. RESULTS: Of the 135 baseline MTB isolates tested, 134 (99%; 95% exact binomial confidence interval, 95.9-99.9%) were susceptible to levofloxacin with an MIC < or = 1.0 microg/ml. We identified a previously unrecognized mis-sense mutation occurring at codon 88 of gyrA in a levofloxacin mono-resistant MTB isolate obtained from a patient with AIDS who had received ofloxacin for 8 months prior to the diagnosis of tuberculosis. CONCLUSIONS: Clinical MTB isolates from HIV-infected patients were generally susceptible to levofloxacin. However, the identification of a clinical isolate with mono-resistance to levofloxacin highlights the need for circumspection in the use of fluoroquinolones in the setting of potential HIV-related tuberculosis and for monitoring of rates of resistance of MTB isolates to fluoroquinolones.

Normalization of CD4+ T-lymphocyte depletion in patients without HIV infection treated for tuberculosis.

A decrease in the number of circulating CD4+ T-lymphocytes occurs in subjects infected with the human immunodeficiency virus (HIV). In those without HIV infection, depletion of T-lymphocytes in general and CD4+ cells in particular has been reported in association with many underlying conditions, including tuberculosis. A low CD4+ T-lymphocyte count at the time of diagnosis of tuberculosis does not clarify whether the low count is a predisposing factor for or a consequence of the disease. Our patients without HIV infection but with tuberculosis and CD4+ T-lymphocyte depletion on presentation normalized their CD4+ cell counts with tuberculosis treatment. This normalization strongly suggests that tuberculosis is a reversible cause of CD4+ lymphocytopenia.

Outbreak of echovirus 11 infection in hospitalized neonates.

Between July 18 and August 5, 1986, a cluster of echovirus 11 infections occurred in hospitalized neonates. Ten infants were affected and one died. All cases occurring after the index case were infants who were in the nursery for at least 1 day when the index patient was also present. Risk factors for secondary infection included low birth weight or gestational age and receipt of antibiotics, red blood cell transfusions, nasogastric intubation or gavage feedings. Because viral infection had not been suspected in the index patient, isolation measures were not instituted until after onset of secondary cases. We conclude that more severely ill infants receiving intensive levels of care are at increased risk for nosocomial enteroviral infection. These infants may have a greater likelihood of exposure to the virus and/or increased host susceptibility. Outbreaks caused by cross-infection may be preventable by early recognition of patients colonized or infected with potentially pathogenic agents and prompt institution of appropriate isolation measures.

Trends in the prevalence of methicillin-resistant Staphylococcus aureus associated with discontinuation of an isolation policy.

The number of patients with methicillin-resistant Staphylococcus aureus (MRSA) before and after discontinuing placement of patients into private rooms was determined. The mean monthly number of patients with MRSA decreased from 34 to 22, and the proportion of S aureus isolates that were MRSA decreased from 34% to 20%. We found no evidence that failure to isolate patients with MRSA resulted in an increased prevalence of MRSA.

Impact of a coordinated tuberculosis Team in an inner-city hospital in New York City.

OBJECTIVE: To evaluate the impact of a coordinated approach for the isolation, diagnosis, and treatment of patients with tuberculosis. DESIGN: Retrospective cohort study. SETTING: Bronx-Lebanon Hospital Center, an inner-city hospital in the South Bronx, New York City. PATIENTS: Patients with smear-positive, culture-confirmed pulmonary tuberculosis. INTERVENTIONS: Institution of a coordinated tuberculosis team. RESULTS: Admissions of 46 patients before and 39 patients after the formation of a tuberculosis team were reviewed. Before institution of the tuberculosis team, 35% of patients were isolated within 24 hours of presentation, 41% never were isolated, and the mean number of days patients were not isolated was 19. After implementation of the tuberculosis team, 59% of patients were isolated within 24 hours, only 5% were never isolated, and the mean number of days patients were not isolated was 3.5. These differences were statistically significant. There also was a corresponding decrease in length of hospitalization. In addition, there were noticeable improvements in patient and staff morale and attitudes. CONCLUSIONS: The tuberculosis team likely has decreased the risk of nosocomial tuberculosis transmission by increasing the proportion of infectious tuberculosis patients admitted into AFB isolation and by reducing (by 780) the number of days out of isolation while smear positive. There also were concomitant financial savings.

Nocardia infection in the acquired immunodeficiency syndrome.

A case of Nocardia asteroides pneumonia in a patient with the acquired immunodeficiency syndrome who was intolerant of sulfadiazine is described. On cefuroxime, the patient had a complete resolution of his Nocardia pneumonia. Disk-diffusion and broth microdilution antibiotic susceptibility testing (MIC less than or equal to 2 micrograms/ml) strongly supported the use of cefuroxime as treatment in this patient. Susceptibility testing with newer cephalosporins should be considered for all significant Nocardia isolates.

The effects of increasing incentives on adherence to tuberculosis directly observed therapy.

SETTING: Six New York State Department of Health tuberculosis (TB) directly observed therapy (DOT) programs in public, private and community facilities in New York City. OBJECTIVE: A key feature of the TB DOT program was provision of incentives to motivate patients and increase adherence to therapy. The study hypothesis was that adherence will improve as the value of incentives increases and bonuses are added in a schedule of increasing rewards. DESIGN: The study population consisted of 365 patients in six inner city TB DOT programs. Interviews, clinical data and attendance records for 3+ years were analyzed. RESULTS: Patients who adhered (attending 80% of prescribed DOT visits each month of treatment) and those who did not were similar on seven demographic factors (e.g., age and sex), but were significantly different on clinical and social variables. Previous TB, resistance to rifampin, human immunodeficiency virus infection, psychiatric illness, homelessness, smoking and drug use were related to non-adherence. High adherence was significantly associated with fewer months in treatment (P < 0.016). Logistic regression showed that the odds that a patient would adhere to therapy were greater with increased incentives. Odds of adherence were significantly lower with rifampin resistance and psychiatric illness. CONCLUSION: Increasing incentives is associated with improved adherence to therapy in inner city TB populations.

Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG), National Institutes for Health.

SETTING: Mortality associated with human immunodeficiency virus (HIV) related multidrug-resistant tuberculosis (MDR-TB) is reduced with effective early therapy. Identifying predictors of, and effective regimens for, MDR-TB is critical. OBJECTIVE: A multicenter prospective study was initiated to 1) determine the demographic, behavioral, clinical and geographic risk factors associated with the occurrence of MDR-TB among HIV-infected patients, and 2) to evaluate the overall survival and clinical response of MDR-TB patients treated with specific drug regimens. METHODS: Patients were prospectively evaluated for MDR-TB. Information included history of prior treatment for tuberculosis, close contact with a known case of MDR-TB, and residence in a facility with known or suspected MDR-TB transmission. Patients with known MDR-TB, or those suspected to be at high risk, were offered enrollment in a treatment pilot study. Study drugs included levofloxacin and at least two additional drugs to which the patient's isolate was known, or most likely, to be susceptible. Survival was the primary endpoint. RESULTS: Complete data are available for 156 HIV-infected patients with confirmed tuberculosis. Sixteen (10%) had MDR-TB. Only a history of prior tuberculosis treatment was associated with MDR-TB in multivariate analysis (OR = 4.4, P < 0.02). Twelve patients with MDR-TB enrolled in the treatment pilot had a median CD4 cell count of 51/mm3. The cumulative probability of survival at one year was 75% (95% CI 50.5-99.5) and at 18 months, 65.6% (95% CI 38.1-93.1). Toxicity requiring discontinuation of medications occurred in two patients. CONCLUSIONS: A history of treatment for tuberculosis was the only predictor for MDR-TB in a cohort of HIV-infected patients with tuberculosis. In addition, this prospective study supports the results of prior retrospective studies that effective treatment impacts on mortality. Current second-line treatment, including high dose levofloxacin, appears to be reasonably well tolerated.

Tuberculosis and human immunodeficiency virus infection.

Mycobacterium tuberculosis infects one third of the world's population, and tuberculosis remains one of the most common infectious diseases of humans. From a global perspective, tuberculosis may be one of the most common HIV-related opportunistic infections. HIV immunosuppression has had a dramatic influence on the epidemiology, natural history and clinical presentation of tuberculosis. Treatment is highly effective for drug susceptible tuberculosis and has been shown to have a significant impact on resistant, especially multidrug-resistant, tuberculosis if started promptly. Directly observed therapy and rigorous adherence to infection control principles have helped control the tuberculosis epidemic in the United States.

Pneumocystosis.

In much of the world, pneumocystosis remains the most common life-threatening opportunistic infection among patients with HIV disease. The infection is caused by Pneumocystis carinii--an organism whose identity as a fungus or parasite is still debated. What is no longer debated, after a decade of AIDS, is that pneumocystosis is almost entirely preventable and eminently treatable. Understanding has improved concerning when prophylaxis should be initiated. It is also recognized that, at least with the agents available today, antiretroviral therapy alone will not prevent pneumocystosis. Sputum induction and the use of monoclonal antibodies have modestly improved our ability to diagnose the infection; however, invasive procedures are still required for most patients, and unusual presentations of the disease, such as cavitary lesions, apical infiltrates, pneumothoraces, and extrapulmonary infection, are not infrequently seen. For treatment, trimethoprim-sulfamethoxazole and intravenous pentamidine remain the mainstays; oral therapy with dapsone and trimethoprim can be as effective as conventional therapy in mild disease, permitting treatment on an outpatient basis. Adjunctive steroids are useful for treatment of moderate to severe pneumocystosis, but clinicians should be alert to the possibility of activation of other latent infections during and after courses of steroids. Both aerosol pentamidine and trimethoprim-sulfamethoxazole are effective prophylaxis. The latter appears to be more effective and costs much less, but the results of comparative trials are not yet available. More data are also needed on the safety, efficacy, and relative advantages of dapsone for prophylaxis. The first decade of the AIDS epidemic has been a decade of progress against pneumocystosis. In the next decade, the emergence of new technologies for diagnosis and of new agents for prophylaxis and treatment will bring us closer to the goal of controlling this serious infection.

Human immunodeficiency virus infection, Part II.

The acceptance of highly active antiretroviral therapy (HAART) among patients and health care providers has had a dramatic impact on the epidemiology and clinical characteristics of many opportunistic infections associated with human immunodeficiency virus (HIV). Previously intractable opportunistic infections and syndromes are now far less common. In addition, effective antibiotic prophylactic therapies have had a profound impact on the risk of patients developing particular infections and on the incidence of these infections overall. Most notable among these are Pneumocystis carinii, disseminated Mycobacterium avium complex, tuberculosis, and toxoplasmosis. Nevertheless, infections continue to cause significant morbidity and mortality among patients who are infected with HIV. The role of HAART in many clinical situations is unquestioned. Compelling data from clinical trials support the use of these therapies during pregnancy to prevent perinatal transmission of HIV. HAART is also recommended for health care workers who have had a "significant" exposure to the blood of an HIV-infected patient. Both of these situations are discussed in detail in this article. In addition, although more controversial, increasing evidence supports the use of HAART during the acute HIV seroconversion syndrome. An "immune reconstitution syndrome" has been newly described for patients in the early phases of treatment with HAART who develop tuberculosis, M avium complex, and cytomegalovirus disease. Accumulating data support the use of hydroxyurea, an agent with a long history in the field of myeloproliferative disorders, for the treatment of HIV. Newer agents, particularly abacavir and adefovir dipivoxil, are available through expanded access protocols, and their roles are being defined and clarified.

Human immunodeficiency virus infection, Part I.

Initially recognized in 1982, acquired immunodeficiency syndrome (AIDS) has been the leading cause of death among young adults in the United States for much of this decade, and it has had a devastating impact on people in the developing world. It is estimated that 42 million people worldwide have been infected with human immunodeficiency virus (HIV), the virus that causes AIDS, and that almost 12 million people have died from AIDS-related diseases through 1997. Among these 12 million are 3 million children. Two thirds of the more than 30 million people with HIV or AIDS reside in sub-Saharan Africa. In the United States, 641,086 patients have been diagnosed with AIDS through 1997, and at least 385,000 have died. However, for the first time, new highly active antiretroviral therapies that include multiple drugs that attack the virus at several sites have slowed the progression from HIV to AIDS and from AIDS to death for those infected with HIV. The cumulative effect of these changes has been a reduction in both AIDS incident cases and AIDS deaths. Recent epidemiologic trends indicate that the proportion of AIDS incident cases and new HIV infections are increasing among women, African-Americans, and Hispanics, and the infections are more likely to be acquired through heterosexual transmission. The clinical management of HIV infection and AIDS has become increasingly complex in recent years. In addition to complete medical and social histories and physical examinations, hematologic, biochemical, serologic, and immunologic laboratory tests are required to predict the likelihood that patients will develop opportunistic infections and other complications related to HIV infection. Among the most important laboratory tests are measurements of HIV in plasma (viral load) in conjunction with peripheral blood CD4+ helper T lymphocyte counts. These tests are potent predictors of disease progression and their results have become markers for clinical response to therapy. The development of highly active antiretroviral therapy has had a profound impact on the epidemiology of AIDS and on the lives of individual patients. Through combinations of antiretroviral drugs, especially protease inhibitors, viral suppression can be achieved. However, adherence to these complex medical regimens and drug interactions have been problems for many patients. In addition, numerous questions remain unanswered, most importantly those regarding the timing of the initiation of treatment, the durability of viral suppression and clinical response, and the optimal "salvage" regimens for patients failing therapy either clinically or virologically.

A randomized comparison of two instruments for measuring self-reported antiretroviral adherence.

A randomised trial compared two instruments for assessing self-reported adherence to antiretroviral medications: (1) a day-by-day recall instrument that elicited the number of missed doses in each of the prior three days (3-day instrument; n=64) and (2) a general recall instrument that elicited an estimate of proportion of pills taken during the prior seven days (7-day instrument; n=70). Adherence was measured at study visits over 12 months among participants in a clinical trial assessing treatment strategies for individuals with virologic failure and multidrug-resistant HIV. Participants had a median (interquartile range) of 133 (41-264) CD4 cells/ml(3) and a median of 10 major HIV resistance mutations at baseline. Mean adherence levels were 90-98% throughout the study. There was a greater trend in the likelihood of 100% adherence when measured by the 3-day versus the 7-day instrument (odds ratio (OR)=1.45; p=0.06). The likelihood of consistent 100% adherence measured by either instrument decreased over time (p<0.001). Participants reporting 100% adherence at more than half of study visits had better virologic and immunologic outcomes at month-12 compared to those reporting 100% adherence at half or fewer visits (HIV RNA decline of 0.96 versus 0.51 log, respectively, p=0.02; and CD4 cell increase of 51.0 versus 17.8 cells, p=0.04). This study demonstrated the utility of the general 7-day recall adherence self-report instrument as well as the 3-day day-by-day recall adherence self-report instrument for measuring antiretroviral adherence. Self-reported adherence was significantly associated with virologic and immunologic outcomes in this population with advanced drug-resistant HIV disease.

Aspergillus species colonization and invasive disease in patients with AIDS.

Invasive aspergillosis is an uncommon infectious complication in patients with AIDS. Of the 972 patients with AIDS who were observed at our institution over a 10-year period, Aspergillus species were isolated from the respiratory sites of 45 patients before death. Invasive aspergillosis was documented at autopsy in four of these patients and was strongly suspected in an additional patient on whom an autopsy was not performed. A fifth case was documented at autopsy (no antemortem respiratory sample was obtained from this patient). Traditional risk factors for the development of invasive disease (neutropenia, hematologic malignancy, and/or corticosteroid use) were present in all of our patients with invasive aspergillosis. A review of the literature revealed reports of an additional 13 cases of invasive aspergillosis in patients with AIDS. Therapy with amphotericin B should be considered for neutropenic patients with AIDS who have pneumonia of uncertain etiology and from whom Aspergillus species have been isolated from a respiratory specimen.

Extrapulmonary Pneumocystis carinii infections.

A case of disseminated infection with Pneumocystis carinii is presented, and the English-language literature is reviewed for cases of documented extrapulmonary infection with this organism. In this case--with P. carinii diffusely replacing the bone marrow and causing hepatic, adrenal, and glomerular tuft necrosis--the clinical illness and multiple-organ dysfunction attributed to disseminated P. carinii were more severe than had previously been described. Because the rate of extrapulmonary P. carinii infection found at autopsy in patients with AIDS is at least 2.5% at our institution, we caution against the routine use of aerosol rather than parenteral pentamidine for treatment of P. carinii pneumonia until additional data are available.