Toxoplasmic encephalitis in AIDS-patients before and after the introduction of highly active antiretroviral therapy (HAART)

Toxoplasmic encephalitis (TE) continues to be a severe health problem despite the introduction of highly active antiretroviral therapy (HAART). To identify predictors for development of TE we compared demographic, clinical and diagnostic variables in AIDS patients with TE before (n = 102) or after the introduction (n = 70) of HAART at the Charité University Medicine in Berlin, Germany. Interestingly, patient characteristics did not differ significantly in the pre- and post-HAART groups. Sixty-eight percent of patients had CD4-cell counts of <50/μl. Outcome after treatment with pyrimethamin plus sulfonamides or clindamycin (47% each) did not differ; adverse reactions were more frequent in patients receiving sulfonamides than in those receiving clindamycin (25% vs. 10.5%; p = 0.02). Interestingly, patients in the post HAART group had not received (82.9%) or had not taken HAART adequately (17.1%). Concurrent diagnosis of TE and HIV was significantly more often in the post- compared to the pre-HAART group (49 vs. 26%, respectively; p > 0.001). Thus, despite the introduction of HAART, awareness of opportunistic infections in HIV patients is warranted. High rates of unawareness of HIV infection should make public health efforts focus on early identification of HIV infection and initiation of and compliance with HAART.     

Clinical and immunologic progression in HIV-infected US women before and after the introduction of highly active antiretroviral therapy

OBJECTIVE: To examine factors associated with clinical and immunologic HIV disease progression in a cohort of US women. DESIGN: Analysis of data from a prospective, longitudinal, case-control study of HIV-infected women followed every 6 months for 7 years. SETTING: Four urban clinical centers in the United States. PARTICIPANTS: 648 HIV-infected women who did not have AIDS at time of entry into the study. MEASUREMENTS: Structured clinical and behavioral interviews; protocol-directed physical examinations; CD4 lymphocyte counts; plasma HIV RNA; infectious pathogen serologies.RESULTS With 2304 women-years of follow-up, 46.1% of the women developed AIDS; however, 93.3% of the diagnoses were based on CD4 counts dropping to <200 cells/mm(3). Only 10.6% of the women with CD4 counts <200 cells/mm(3) developed an opportunistic infection. Baseline CD4 count was the strongest predictor of subsequent clinical progression. Illicit substance use, multiple pregnancies, demographic variables, and other infections were not associated with progression. Among women with CD4 counts >500 cells/mm(3) at baseline, those who were anemic or had hepatitis C were more likely to progress to AIDS. By the end of the study, only 52% of the participants were on highly active antiretroviral therapy (HAART). CONCLUSIONS: Despite underutilization of HAART in this multicenter cohort of urban women, opportunistic infections were uncommon, despite CD4 declines.     

Immune function and phenotype before and after highly active antiretroviral therapy.

Immune functions represented by equal CD4 counts before and after highly active antiretroviral therapy (i.e., pre- and post-HAART) in the same HIV-infected patients, were examined. Twelve HIV-infected patients were included. Patients had equal CD4 counts pre- and post-HAART and were studied on average 30 months pre-HAART and 17 months post-HAART. Post-HAART, CD8+ T cells expressed greater amounts of CD28 (p < .02), smaller amounts of CD38 (p < .02), and a reduced proportion of CD4+CD28+ T cells expressed CD38+ (p < .01). Proliferation increased (p < 10) in lymphocyte cell cultures stimulated with pokeweed mitogens or Candida, and was correlated to expression of CD28 on T cells (p < .02). The proportion of CD3-CD16-CD56+ natural killer (NK) cells increased (p < .05) and CD3-CD16+CD56- NK cells declined (p < .01). Production of interferon-gamma increased (p < .10). The number of naive and memory T cells, the non-major histocompatibility complex (non-MHC)-restricted and HIV-specific MHC-restricted cytotoxicity and the production of macrophage inflammatory protein-1gamma were unchanged. The finding of increased expression of CD28, correlating to increased proliferation capacity, and diminished expression of CD38 on T cells, indicates that following long-term HAART, repopulation occurs with less activated cells with increased proliferative capacity. This finding may be of clinical importance in considering risk and vulnerability for progression of opportunistic infections post-HAART.     

Hospitalization rates in an urban cohort after the introduction of highly active antiretroviral therapy

OBJECTIVE: Previous studies have shown a decrease in hospitalization rates associated with the introduction of highly active antiretroviral therapy (HAART). To evaluate hospitalization rates and patterns in discharge diagnoses that changed between 1995 and 1998 and to examine risk factors for hospitalization in HIV-positive patients, we conducted a cohort study. PATIENTS AND METHODS: All inpatient hospitalizations of 2,151 HIV-positive patients enrolled in our university-based HIV clinic between January 1, 1994 and December 31, 1998 with a CD4 count within a 6-month calendar semester were examined to evaluate hospitalization rates, discharge diagnoses, and intensive care department use. Negative binomial regression was used to assess the effect of various risk factors on hospitalization. RESULTS: Hospitalization rates decreased between 1995 and 1996 but increased between 1997 and 1998. In multivariate regression, female gender (incidence rate ratio [IRR], 1.45; p <.001), injection drug use (IRR, 1.36; p <.001), and having received no antiretroviral therapy were strong predictors of total hospitalization. White race, low CD4 count, and no antiretroviral treatment were strong predictors of hospitalization for an opportunistic infection. Female gender (IRR, 1.45; p <.001), African-American ethnicity (IRR, 1.22, p =.05), no antiretroviral treatment, and low CD4 counts were predictive of higher hospitalization rates for nonopportunistic infection-related diagnoses. Intensive care department-use was associated with white ethnicity (IRR, 1.86; p =.028), heterosexual transmission of HIV (IRR, 1.90; p =.009), no antiretroviral treatment, and low CD4 count at enrollment. CONCLUSIONS: Our data indicate that hospitalization rates decreased between 1995 and 1997 after introduction of HAART, but that they then increased between 1997 and 1998, particularly for diagnosed nonopportunistic infections. If these trends continue, it indicates that patients may be developing previously unseen comorbidities and that HAART may have reached or exceeded a threshold in its effectiveness in reducing the clinical morbidity that results in hospital admission.     

Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors

OBJECTIVES: To assess complete remission (CR) and survival in patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) receiving highly active antiretroviral therapy (HAART). METHODS: We analyzed the Grupo de Estudio del SIDA register of systemic ARL, which started in Jan 1994, to collect cases diagnosed at 15 institutions prospectively and with active follow-up every 6 months. The date of censorship for this study was March 2005. RESULTS: During the study period, 210 consecutive patients were diagnosed with ARL, with a median age 39 of years, 75.7% of whom were male, and with a median baseline CD4 count of 160 cells/microL. Histologic subtypes were diffuse large B-cell lymphoma (DLCL; n = 153 [72.9%]), Burkitt and atypical Burkitt/Burkitt-like lymphoma (BL; n = 40 [19.0%]), T-cell lymphoma (TC; n = 8 [3.8%]), and miscellaneous (n = 9 [4.3%]). Chemotherapy with or without other modalities was administered to 186 (88.6%) patients. In an intent-to-treat analysis of 184 patients who received at least 1 chemotherapy course with adequate follow-up to assess their response, 119 (64.7%) achieved CR, and the median length of survival (Kaplan-Meier analysis) was 52 months (95% confidence interval [CI]: 23 to 82 months). Factors independently associated with CR were histologic subtype and International Prognostic Index (IPI) score. Factors independently associated with improved overall length of survival (OS) were CR, low IPI score, and histologic subtype. The single factor independently associated with disease-free survival was Ann Arbor stage. CONCLUSIONS: In patients with ARL treated with HAART, CR was associated exclusively with tumor-related factors. The CR rate was poorer in patients with BL and TC subtypes and was inversely correlated with IPI score. OS was independently associated with CR, IPI score, and the histologic subtype.     

Remission of HIV-associated myelopathy after highly active antiretroviral therapy

HIV-associated myelopathy is the leading cause of spinal cord disease in HIV-infected patients. Typically, it affects individuals with low CD4 T cell counts, presenting with slowly progressive spastic paraparesis associated with dorsal column sensory loss as well as urinary disturbances. Other aetiologies must be first ruled out before establishing the diagnosis. We report here the case of a 37-year-old woman with advanced HIV disease, who developed HIV-associated myelopathy. The patient showed a gradual improvement after beginning with highly active antiretroviral therapy and, finally, she achieved a complete functional recovery. In addition, neuroimaging and neurophysiological tests normalized.     

Gender and hospitalization patterns among HIV-infected drug users before and after the availability of highly active antiretroviral therapy

We examined highly active antiretroviral therapy (HAART) era and pre-HAART era hospitalization rates among 604 HIV-infected drug users in a prospective study in Bronx, New York. Medical history and risk behaviors were elicited by semiannual interviews. Standardized medical record review abstracted discharge diagnoses for all hospitalizations. Hospitalization rates from January 1997 to December 2000 were compared with rates from January 1992 to December 1996. The rate of hospitalizations per 100 patient-years in the HAART era was 49.3 compared with 44.1 in the pre-HAART era (P = 0.13). Among women, the rate was significantly higher in the HAART era than in the pre-HAART era (68.1 vs. 49.4 hospitalizations per 100 patient-years, respectively; P = 0.01). In the second era, HAART users had lower rates than those who did not use HAART (37.2 vs. 83.4 hospitalizations per 100 patient-years, respectively; P < 0.001) for both HIV-associated and non-HIV-associated illnesses. Multivariate analysis revealed that in the HAART era, female gender (relative risk ratio = 1.72, P = 0.03) and not using HAART (relative risk ratio = 1.82, P = 0.02) independently predicted increased hospitalization risk. In the pre-HAART era, women were at independently higher risk of hospitalization (relative risk ratio = 1.36, P = 0.05). Among HIV-infected drug users, those who use HAART have a decreased risk of hospitalization; those who do not use HAART remain at high risk of continuing morbidity from both HIV-related and non-HIV-related illness and have high hospitalization rates.     

The impact of hepatitis C virus coinfection on HIV progression before and after highly active antiretroviral therapy

To compare the impact of hepatitis C virus (HCV) coinfection on progression of HIV infection in the eras before and after the introduction of highly active antiretroviral therapy (HAART), the authors conducted a retrospective cohort study. One hundred twenty-five HCV+ patients and 1076 HCV- patients were studied; 83% of HCV+ patients were injection drug users. HCV+ subjects experienced no clear benefit from HAART. The adjusted hazard ratios (HRs) of opportunistic infection, death, and hospitalization were 0.74 (95% CI: 0.31-1.78), 1.78 (95% CI: 0.59-5.37), and 2.1 (95% CI: 0.90-4.90), respectively, comparing the post-HAART era with the pre-HAART era. In contrast, HCV- subjects experienced rate reductions for all outcomes. Comparable HRs for opportunistic infection, death, and hospitalization were 0.49 (95% CI: 0.37-0.64), 0.28 (95% CI: 0.19-0.41), and 0.51 (95% CI: 0.38-0.67), respectively. HCV+ subjects remained at increased risk for death and hospitalization post-HAART even after additional adjustment for antiretroviral use and time-updated CD4 cell and viral load measures. Deaths and hospitalizations in HCV+ patients were primarily for non-AIDS-defining infections and complications of injection drug use. HCV coinfection and comorbidity associated with injection drug use are preventing the realization of substantial health benefits associated with HAART.     

Immunological analysis of treatment interruption after early highly active antiretroviral therapy

We longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a low plasma viral load (<15,000 copies/mL), whereas others could not (>50,000 copies/mL). Before HAART was initiated, plasma viral load was similar. After TI, the numbers of CD8(+) T cells increased more in individuals without viral control, whereas individuals maintaining a low viral load showed a more pronounced increase in HIV-specific CD8(+) T-cell numbers. No differences were seen in the number or percentage of cytokine-producing HIV-1-specific CD4(+) T cells, or in proliferative capacity of T cells. Four weeks after TI, the magnitude of the total HIV-1-specific CD8(+) T-cell response (IFN-γ(+) and/or IL-2(+) and/or CD107a(+)) was significantly higher in individuals maintaining viral control. Degranulation contributed more to the overall CD8(+) T-cell response than cytokine production. Whether increased T-cell functionality is a cause or consequence of low viral load remains to be elucidated.     

Treatment-related factors and highly active antiretroviral therapy adherence

Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV-infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment-related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short- and long-term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART-treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patient's specific lifestyle, and anticipation and self-management of side effects are treatment-based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well-tolerated antiretroviral treatment.     

Health-related quality of life after 1 year of highly active antiretroviral therapy

OBJECTIVE: We investigated the impact of the first year of highly active antiretroviral therapy (HAART) on health-related quality of life (HRQL). METHODS: Medical data for patients in the French APROCO cohort were collected at enrollment (M0) and month 12 (M12). A self-administered questionnaire gathered information about HRQL (Medical Outcome Study 36-Item Short Form Health Survey) and toxicity-related symptoms. Using the twenty-fifth percentile of HRQL scales in the French population as a threshold, patients with normal values in at least three mental and three physical scales were considered to have a "normal HRQL." RESULTS. Of the 1053 patients followed through M12, HRQL data at M0 and M12 were available for 654. Among the 233 patients with a normal baseline HRQL, 63 (27.0%) experienced a deterioration of HRQL at M12. Among the 421 patients with a low baseline HRQL, 121 achieved a normal HRQL at M12. Logistic regression showed that factors independently associated with a normal HRQL at M12 were normal baseline HRQL, baseline CD4 count <500 cells/mm, time since HIV diagnosis <8 years, undetectable HIV-RNA at M12, and lower number of self-reported symptoms at M12. CONCLUSION: An assessment of HRQL should be integrated to efficacy outcomes to evaluate and compare long-term strategies properly and to optimize the durability of response to antiretroviral therapy.     

Sexual dysfunction in the highly active antiretroviral therapy era

The possible relationship between HAART and the development of sexual disturbances of HIV-infected patients remains yet unresolved because of the inconsistency of the results of the different studies. To analyze the current knowledge on this topic, MEDLINE files were searched for articles dealing with any manifestation of sexual dysfunction in the HAART era. Selected references from these articles as well as communications to the main HIV meetings were also reviewed. Sexual dysfunction seems to be a very common event after the introduction of HAART. The average prevalences of sexual dysfunction among the different studies was 51%, erectile dysfunction 46%, decreased libido 44%, ejaculatory disturbances 39% and orgasmic disorders 27%. These disturbances seemed to be more common in patients treated with protease inhibitors. Several relevant questions related to sexual dysfunction in these patients are addressed in this review, including the possible pathogenic mechanisms involved. Despite the inconsistent results among the studies, the data that support a direct or indirect role of HAART in the generation of these disturbances seem to exceed the data that do not support it. As a conclusion, antiretroviral therapy, particularly protease inhibitors, seems to be to some extent directly or indirectly related to sexual dysfunction through different mechanisms.     

Changing clinical presentation and survival in HIV-associated tuberculosis after highly active antiretroviral therapy

OBJECTIVE: To assess changes in clinical presentation and outcome of HIV-associated tuberculosis (TB) before and after widespread implementation of highly active antiretroviral therapy (HAART). METHODS: We reviewed clinical charts of HIV-infected patients with culture-confirmed pulmonary TB in two referral clinical centers in Rome, Italy. The 67 patients diagnosed in 1995 to 1996 were compared with 51 patients diagnosed in 1997 to 1998. To analyze factors associated with survival we used a Cox model including antiretroviral therapy as a time-dependent covariate. RESULTS: Patients diagnosed in 1997 to 1998 were more likely to have TB as the first AIDS-defining illness (78% versus 58%, p <.05), to have HIV diagnosed <2 months before TB (33% vs. 7%, p <.005) and to have typical chest radiograph pattern (45% vs. 25%, p <.05), and had a higher CD4(+) count (median 105 vs. 43, p <.005). Survival at 1 year was 80% for patients diagnosed in 1997 to 1998 vs. 65% for those diagnosed in 1995 to 1996 (p by log-rank =.02). After adjusting at multivariate analysis, time period of diagnosis was not confirmed as associated with survival (hazard ratio, 1.05; 95% confidence interval, 0.39--2.81). Age, CD4+ cell count <25/mm(3), and AIDS-defining illnesses before TB diagnosis were all associated with an higher risk of death, whereas a decreased risk of death was observed in patients starting a triple combination antiretroviral therapy after TB diagnosis (hazard ratio, 0.14; 95% confidence interval, 0.03--0.57). CONCLUSIONS: Cases of HIV-associated TB occurring in patients with advanced immunosuppression and presenting with atypical radiologic appearance tend to be relatively less common in the HAART era. HAART is a major factor in prolonging survival in these patients.     

Virologic and immunologic response to highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) delays clinical progression by suppressing viral replication, measured by a substantial reduction in HIV RNA, allowing the immune system to reconstitute, measured in most studies by an increase in CD4 cells. These virologic and immunologic consequences do not occur uniformly among HAART users. Markers of HIV disease stage at the time of HAART initiation are critical determinants of the progression while receiving HAART. In this report, we review studies describing the heterogeneous virologic and immunologic progression after the initiation of HAART, discuss methodologic concerns in the study of the response of biomarkers, and update findings obtained in the Multicenter AIDS Cohort Study, which show that CD4 cell count, history of antiretroviral therapy, and age at the time of initiation are independent determinants of response.     

Cytomegalovirus retinitis in the era of highly active antiretroviral therapy

Cytomegalovirus (CMV) is a common opportunistic infection in individuals with AIDS. Moreover, CMV retinitis represents a significant portion of end-organ disease in patients with CMV and AIDS. Prior to the advent of highly active antiretroviral therapy (HAART), almost one-third of people with AIDS developed CMV retinitis during their lifetime. Although effective therapies for CMV infection had been developed, treatment was often life-long due to persistent immune deficiency. Despite chronic suppressive maintenance therapy, disease relapse was nearly universal, and development of drug resistance was not uncommon. Widespread use of HAART has reduced the incidence and complications of CMV retinitis. With sustained immune recovery, discontinuation of anti-CMV therapy has been possible in many patients. Still, immune recovery does not guarantee protection from recurrent disease. CMV retinitis and uveitis associated with immune recovery remain causes of vision loss in this population and demand vigilance on the part of physicians.