Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.     

A comparison of exposure groups in the EuroSIDA study: starting highly active antiretroviral therapy (HAART), response to HAART, and survival

BACKGROUND: Concerns have been raised that intravenous drug users may be less likely to start highly active antiretroviral therapy (HAART) and that adherence to therapy may be poor among this group of patients. Given the decreased mortality and incidence of AIDS-defining illnesses among patients with HIV who start HAART, this may lead to a poorer prognosis among intravenous drug users. PURPOSE: To compare homosexual men, intravenous drug users, and heterosexuals in EuroSIDA, a prospective European cohort of 7331 patients with HIV in terms of starting a HAART treatment regimen, immunologic and virologic response to therapy, and survival. METHODS: 6645 patients were included in this analysis. Logistic regression and Cox proportional hazards models were used to investigate the factors associated with use of HAART regimens and survival following recruitment to the EuroSIDA study. RESULTS: In a multivariate logistic regression model, intravenous drug users were significantly less likely to be receiving HAART at recruitment to EuroSIDA (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.37-0.62; p<.0001) when compared with homosexual men. Similarly, during follow-up, intravenous drug users were at a 27% reduced risk of starting HAART, after adjustment for other factors related to starting HAART (relative hazard [RH], 0.73; 95% CI, 0.64-0.82; p<.0001). There were no differences between heterosexual and homosexual patients, and similar results were found within regions of Europe (South, Central and Northern). Among those patients who started HAART, there were no significant differences between exposure groups in CD4 lymphocyte count response to HAART or virologic response to HAART. After adjustment for factors related to survival, intravenous drug users were at a small, but nonsignificant increased risk of death compared with homosexuals (RH 1.16; 95% CI, 0.99-1.38; p = .074). CONCLUSIONS: Intravenous drug users were significantly less likely to start HAART, but among those who did, response to therapy was similar to that of other exposure groups. There were no differences in risk of death. If intravenous drug users continue to use HAART less commonly than other exposure groups, it may result in a poorer prognosis, a different spectrum of AIDS-defining illnesses, and differential long-term clinical needs.     

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.     

The association of race, sociodemographic, and behavioral characteristics with response to highly active antiretroviral therapy in women

OBJECTIVE: To determine the association of race with clinical and laboratory outcomes after initiation of highly active antiretroviral therapy (HAART) in HIV-1-infected women in the United States. STUDY DESIGN: Prospective cohort study. PARTICIPANTS: A total of 961 HIV-1-infected women participating in the Women's Interagency HIV Study initiating HAART between July 1, 1995 and September 30, 2003. RESULTS: Over a median of 5.1 years of follow-up, in univariate Cox regression analyses, white women were more likely than African American women to attain a virologic response (relative hazard [RH]=1.34, P=0.005), less likely to experience viral rebound (RH=0.76, P=0.051), and less likely to die (RH=0.63, P=0.040). There were no significant differences, however, among racial groups in outcomes after adjustment for pre-HAART CD4, HIV-1 RNA, history of AIDS-defining illness, age, antiretroviral therapy use, baseline HIV-1 exposure category, and post-HAART behavioral and clinical variables associated with poorer response (discontinuation of HAART, lower income, smoking, current drug use, and depression). Continuous HAART use and lack of depression differed by race and were the strongest predictors of favorable outcomes. CONCLUSION: No significant differences by race were found in virologic, immunologic, or clinical outcomes after adjustment for continued HAART use and depression. These findings suggest that strategies to enhance HAART continuation, including assessing pharmacogenetic influences that may result in greater toxicity and discontinuation rates, and treating depression can improve individual and population-based effects of treatment and potentially mitigate racial disparities in AIDS-related outcomes.     

Survival in an urban HIV-1 clinic in the era of highly active antiretroviral therapy: a 5-year cohort study

OBJECTIVE: To examine the implications of early virologic response to highly active antiretroviral therapy (HAART) on long-term HAART utilization patterns, development of diabetes or hyperlipidemia, and mortality in an urban HIV-1 clinic. DESIGN: A cohort of 444 patients in an urban HIV-1 clinic, who started HAART prior to January 1, 1999, were categorized by virologic response in the first 18 months of therapy: durable viral suppression, initial suppression followed by rebound, and failure to achieve suppression. Antiretroviral exposure, HIV-1 RNA levels, CD4 cell counts, development of diabetes or hyperlipidemia, and survival were compared in the three groups. RESULTS: Over 4 years of follow-up, patients in the durable suppression group used HAART 82% of the time compared with 60% in the rebound group (p <.001) and 23% in the failure to suppress group (p <.001). Through 4 years of follow-up, patients in the rebound group had a cumulative exposure to a median of seven antiretroviral drugs (interquartile range [IQR]: 6-9) compared with five drugs in the durable suppression group (IQR: 4-6) and five drugs in the failure to suppress group (IQR: 3-7) (p <.001 for both comparisons with the rebound group). At 5 years, the estimated proportions surviving were 89% in the durable suppression group, 76% in the rebound group (p =.04), and 56% in the failure to suppress group (p <.001). During follow-up, 35% in the durable suppression group developed diabetes or hyperlipidemia compared with 24% in the rebound group (p =.15) and 8% in the failure to suppress group (p <.001). CONCLUSIONS: This study highlights the long-term implications of early virologic response to HAART for survival, accumulation of triple-class antiretroviral exposure, and development of HAART-associated toxicities.     

Response to highly active antiretroviral therapy according to duration of HIV infection

OBJECTIVE: To evaluate whether duration of HIV-1 infection influences the response to highly active antiretroviral therapy (HAART). DESIGN: Prospective study of individuals (Italian Seroconversion Study cohort) with well-estimated dates of HIV-1 seroconversion. METHODS: This analysis included 277 participants who began HAART (defined as three antiretroviral drugs used in combination). Cox regression models were used to evaluate the association between duration of infection (as categorical variable [7.5 years from seroconversion] or continuous variable) and an immunologic (rise in CD4 count >100 cells/mm3) and a virologic (decline in plasma HIV-RNA to unquantifiable levels) outcome. All analyses were stratified by center of recruitment and adjustment, when used, was for gender, age at inception of HAART, injection drug use, previous antiretroviral therapy, lag-time between positive and negative HIV test result, year of starting HAART, clinical stage, CD4 count, and HIV-RNA at time of HAART. RESULTS: HAART was initiated a median of 6.4 years after seroconversion. There was a median follow-up of 1.6 years after starting HAART to the calendar cut-off (November 1999). One-hundred-eighty-one (65.3%) patients experienced a decline in viral load to below quantifiable levels and 184 (66.4%) experienced a rise in CD4 >100 cells/mm3. In the Cox models, by 1-year increase in duration of infection, we estimated a lower crude hazard of achieving a CD4 count increase >100 cells (relative hazard [RH], 0.96; 95% confidence interval [CI], 0.92-1.01; p =.09), and a lower hazard of reaching an unquantifiable level of plasma HIV-RNA (RH, 0.97; 95%CI, 0.93-1.02; p =.20). After adjustment, these values became 0.99 (95%CI, 0.93-1.04; p =.62) and 0.98 (95%CI, 0.93-1.04; p =.48), respectively. When duration of HIV infection was considered as a categorical variable, the results were consistent with those already described. CONCLUSIONS: These results suggest that the duration of HIV infection does not seem to play an important independent role in determining the virologic and immunologic responses to HAART.     

Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection

OBJECTIVE: To compare the long-term prognostic significance of different definitions of immunologic and virologic responses to highly active antiretroviral therapy (HAART) at 6 months. METHODS: This was a prospective study conducted in 68 French hospitals. HAART was initiated in 2236 protease inhibitor-naive patients included in the French Hospital Database on HIV. Multivariate Cox proportional hazard models measuring time from 6 months after starting HAART were used to compare the strength of the association between different definitions of immunologic and virologic responses at 6 months and subsequent progression to AIDS or death. The Akaike's Information Criteria were used to identify the most appropriate model. RESULTS: During a median follow-up of 58 months, 325 patients experienced an AIDS-defining event or died. The model that fitted best was the model in which the CD4 cell count and plasma HIV-1 RNA values attained at 6 months were considered. The risk of clinical progression at 5 years ranged from 7% (95% confidence interval [CI]: 4-10) in patients whose CD4 cell count at 6 months was >or=350 cells/microL and whose HIV-1 RNA concentration was <3 log10 copies/mL to 63% (95% CI: 52-75) in patients whose CD4 cell count at 6 months was <100 cells/microL and whose HIV-1 RNA concentration was >or=5 log10. CONCLUSIONS: Plasma HIV-1 RNA concentration and CD4 cell count should be taken into account independently when evaluating early response to treatment. The persistent impact of early response on clinical progression at 5 years emphasizes the major importance of the success of first-line HAART.     

Virological and Immunological Response to HAART Therapy in a Community-Based Cohort of HIV-1-Positive Individuals

Abstract

Purpose: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. Method: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. Results: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/μL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. Conclusion: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.     

Antiretroviral Genotypic Resistance Mutations in HIV-1 Infected Korean Patients with Virologic Failure

Resistance assays are useful in guiding decisions for patients experiencing virologic failure (VF) during highly-active antiretroviral therapy (HAART). We investigated antiretroviral resistance mutations in 41 Korean human immunodeficiency virus type 1 (HIV-1) infected patients with VF and observed immunologic/virologic response 6 months after HAART regimen change. Mean HAART duration prior to resistance assay was 45.3±27.5 months and commonly prescribed HAART regimens were zidovudine/lamivudine/nelfinavir (22.0%) and zidovudine/lamivudine/efavirenz (19.5%). Forty patients (97.6%) revealed intermediate to high-level resistance to equal or more than 2 antiretroviral drugs among prescribed HAART regimen. M184V/I mutation was observed in 36 patients (87.7%) followed by T215Y/F (41.5%) and M46I/L (34%). Six months after resistance assay and HAART regimen change, median CD4+ T cell count increased from 168 cells/µL (interquartile range [IQR], 62-253) to 276 cells/µL (IQR, 153-381) and log viral load decreased from 4.65 copies/mL (IQR, 4.18-5.00) to 1.91 copies/mL (IQR, 1.10-3.60) (P<0.001 for both values). The number of patients who accomplished viral load <400 copies/mL was 26 (63.4%) at 6 months follow-up. In conclusion, many Korean HIV-1 infected patients with VF are harboring strains with multiple resistance mutations and immunologic/virologic parameters are improved significantly after genotypic resistance assay and HAART regimen change.     

Self-reported adherence to antiretroviral therapy for HIV-1 infection and virologic treatment response: a meta-analysis

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for HIV-1 infection is essential for plasma HIV-1 RNA suppression. Self-report is the most frequently used measure of adherence to HAART, but its validity is controversial. Studies on the relation between self-reported adherence and virologic treatment response have shown inconsistent results. We investigated whether this variability between studies about the effect of self-reported adherence on virologic treatment response could be attributed to study design features. METHODS: We searched for studies reporting on adult nonpregnant patients prescribed antiretroviral therapy for chronic HIV-1 infection using a self-reported adherence measure and providing information about the relation between adherence and plasma HIV-1 RNA concentrations. Meta-analysis with random effects modeling was used to pool data and to investigate sources of heterogeneity. RESULTS: Sixty-five studies fulfilled inclusion criteria, containing data from 15,351 patients. The pooled odds ratio (95% confidence interval) of detectable plasma viral load in nonadherent patients was 2.31 (1.99-2.68). There was significant heterogeneity among studies (P < 0.001). Not ascertaining confidentiality of responses, use of actual viral load measurements, an adherence threshold lower than 95%, higher percentages of patients on their initial antiretroviral regimen, and higher percentages of patients with a history of intravenous drug use within a study were associated with higher point estimates. CONCLUSIONS: Overall, we observed that self-reported adherence measures can distinguish between clinically meaningful patterns of medication-taking behavior. Distinct study characteristics were significantly associated with the relation between adherence and virologic response. These characteristics should be taken into consideration when interpreting results from studies on self-reported adherence.     

Nonadherence among HIV-infected injecting drug users: the impact of social instability

The authors tested the impact of social instability on adherence to highly active antiretroviral therapy (HAART) among patients infected with HIV through injection drug use (IDU; MANIF2000 cohort). In the study, they analyzed sociodemographic baseline characteristics to develop an indicator of social instability. Information concerning adherence to HAART was collected through questionnaires during a 2-year follow-up period. Factors associated with nonadherence were studied in two different groups: 1) patients who had stopped injection drug use (ex-IDUs) and who were not in drug maintenance programs (DMT) during the entire follow-up period, and 2) those who were still opiate dependent. Among the 210 eligible patients, 114 were classified as ex-IDUs and 96 as opiate dependent. Ex-IDUs reported nonadherence behaviors in 96 of 384 visits (25.0%), while opiate-dependent patients were nonadherent in 111 of 308 visits (36.0%; p = .02). Among ex-IDUs, the only factor associated with nonadherence was social instability, while among opiate-dependent patients, injection behavior was the only determinant of nonadherence behavior. For opiate-dependent patients, DMT may enhance adherence to HAART, but only if it is successful in reducing abuse of injection practices. For ex-IDUs, it is very important that the management of social difficulties be taken into account to increase adherence to HAART.     

HIV-infected patients receiving lopinavir/ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%

BACKGROUND: The observation that extremely high levels of medication adherence are required to achieve complete virologic suppression is based largely on studies of treatment-experienced patients receiving HIV protease inhibitor (PI)-based therapy without ritonavir boosting. This study aims to define the level of adherence needed to achieve virologic suppression in patients receiving boosted PI-based highly active antiretroviral therapy (HAART) with lopinavir/ritonavir. METHODS: HIV-infected adults receiving a regimen containing lopinavir/ritonavir were recruited into a prospective, observational study of the relation between adherence to lopinavir/ritonavir and virologic outcomes. Adherence was measured using the Medication Event Monitoring System (MEMS; Aardex, Union City, CA). HIV-1 viral load (VL) was measured at week 24. RESULTS: The final study population contained 64 subjects. Eighty percent had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more than 7 years of HAART experience. Mean adherence overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a VL <75 copies/mL, respectively. Mean adherence was 75% in those achieving a VL <75 copies/mL. High rates of virologic suppression were observed in all adherence quartiles, including the lowest quartile (range of adherence: 23.5%-53.3%). CONCLUSIONS: Moderate levels of adherence can lead to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.     

Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences

OBJECTIVE: To characterize the magnitude and the predictors of highly active antiretroviral therapy (HAART) interruption (TI) and to investigate its immunologic and virological consequences. METHODS: Using Concerted Action on Seroconversion to AIDS and Death in Europe data from 8,300 persons with well-documented seroconversion dates, we identified subjects with stable first HAART (for at least 90 days) not initiated during primary infection. A TI was defined as an interruption of all antiretroviral therapy drugs for at least 14 days. RESULTS: Of 1,551 subjects starting HAART, 299 (19.3%) interrupted treatment. Median (interquartile range) duration of the TI was 189 (101-382) days. The cumulative probability (95% confidence interval) of TI at 2 years was 15.9% (14.0%-18.1%). Women were more likely to have a TI than men in the same exposure group (35.8% vs 24.2% among drug users, 22.1% vs 13.3% among heterosexuals; P < 0.05). Higher baseline viremia and poor immunologic response to HAART were associated with higher probabilities of TI. Median (interquartile range) individual CD4 cell loss during TI was 94 (1-220) cells/microL. Older age at HAART (>40 yr), lower pre-HAART nadir (<200 cells/microL), and lower CD4 at start of TI (<350 cells/microL) were significantly associated with greater relative CD4 loss during TI. CONCLUSIONS: We estimate that almost 1 in 6 subjects on HAART interrupts treatment by 2 years. Further research is needed to investigate the reasons why TI is higher in women. We have identified characteristics of subjects with the greatest risk for CD4 loss in whom TI may have greater risks.     

Immunity to human immunodeficiency virus (HIV) in children with chronic HIV infection receiving highly active antiretroviral therapy

Our objective was to describe the CD4-mediated human immunodeficiency virus (HIV)-specific cell-mediated immunity (CMI) and its virologic and immunologic correlates in children with chronic HIV infection on highly active antiretroviral therapy (HAART). Twelve HIV-infected children on stable antiretroviral therapy with a median level of CD4+ lymphocytes (CD4%) of 25.5% and a median viral load (VL) of 786 HIV RNA copies/ml were enrolled in this study. Nine of these children were also cytomegalovirus (CMV) seropositive. Blood mononuclear cells, stimulated with HIV and CMV antigens, were used to measure lymphocyte proliferation and to enumerate gamma interferon (IFN-gamma)-producing CD4+ cells. HIV CMI and CMV CMI were detected in similar proportions of patients and correlated with each other, although the HIV responses were less robust. HIV lymphocyte proliferation significantly increased with lower HIV VL and showed a trend to increase with higher CD4% and longer time on HAART. The in vitro IFN-gamma response to HIV or CMV was not affected by CD4%, VL, or HAART. Pediatric patients with established HIV infection on HAART frequently exhibit HIV CMI despite undetectable HIV replication. We concluded that the association between HIV CMI and CMV CMI indicates that the same factors govern responsiveness to either antigen.     

Interleukin-7 and immunologic failure despite treatment with highly active antiretroviral therapy in children perinatally infected with HIV-1

Baseline interleukin-7 (IL-7) level has been proposed as a predictor of immunologic response to antiviral therapy, and the use of exogenous IL-7 has been suggested in the treatment of HIV-infected patients. Therefore, we investigated the relationships between IL-7 serum levels and immunologic outcome of highly active antiretroviral therapy (HAART) in 24 children perinatally infected with HIV-1. IL-7 serum levels were evaluated by enzyme-linked immunosorbent assay before switching antiretroviral treatment from double therapy to HAART and then again after 12 weeks of HAART. Differences were analyzed between children with immunologic failure and those without. At baseline, IL-7 levels were significantly higher in HIV-1-infected children than in 24 healthy age-matched uninfected children (16.6 +/- 8.7 vs. 9.5 +/- 2.4 pg/mL, respectively; P < 0.001). IL-7 levels inversely correlated with CD4 T-lymphocyte percentage both at baseline (r = -0.71, P < 0.001) and after 12 weeks of HAART (r = -0.49, P = 0.01). We observed no correlation between IL-7 levels and viral load (r = 0.29, P = 0.17 at baseline; r = 0.30, P = 0.15 after 12 weeks). Baseline IL-7 levels were similar in HIV-1-infected children with or without subsequent immunologic failure (15.1 +/- 8.8 vs. 17.5 +/- 8.7 pg/mL, respectively; P = 0.75). After 12 weeks of HAART, IL-7 levels were 21.6 +/- 13.5 pg/mL in children with immunologic failure (P = 0.08 when compared with baseline levels) and 8.2 +/- 3.8 pg/mL in children without immunologic failure (P = 0.002 when compared with baseline levels). IL-7 levels were significantly higher (P = 0.003) in children with immunologic failure than in those without. Findings indicate that baseline IL-7 serum levels do not predict immunologic outcome of HAART and that immunologic failure occurs even in the presence of high IL-7 serum levels, thus suggesting no benefit from therapy with exogenous IL-7.