Dissociation of immunologic and virologic responses to highly active antiretroviral therapy

OBJECTIVE: Immunologic markers, levels of HIV DNA, and infectious HIV were compared in partial responders (PR) to HAART who had high plasma HIV RNA levels but stable or increasing levels of CD4+ peripheral blood mononuclear cells (PBMC), and patients with complete failure (CF) who had very low or decreasing levels of CD4+ PBMC and high plasma HIV RNA levels. DESIGN AND METHODS: CD4 and CD8 levels were monitored by flow cytometry. Beta2-microglobulin (beta2M) and neopterin levels were measured by quantitative enzyme immunoassays. Plasma and PBMC from 11 PR and 13 CF were analyzed for infectious HIV levels in limiting dilution cultures. Polymerase chain reaction (PCR) assays were used to quantify cellular HIV DNA and plasma HIV RNA. RESULTS: In comparison with CF, PR had little or no CD4+ cell loss, a substantial increase in CD8+ cells, significantly fewer positive plasma HIV cultures (p = .03), lower frequencies of infectious HIV in total PBMC (p = .005) and in CD4+ PBMC (p < .001), and lower frequencies of HIV DNA in CD4+ PBMC (p = .007). CONCLUSIONS: Lower levels of infectious HIV and a lower frequency of CD4+ PBMC that contain "productive" HIV DNA in PR as compared with CF may contribute to the stable or increasing CD4+ PBMC levels of the PR. However, HAART may also have effects on lymphocyte homeostasis independent of its antiviral activity.     

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.     

Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy

BACKGROUND: The prognostic significance of a response to highly active antiretroviral therapy (HAART) that is immunologically and virologically discordant is not well understood. METHODS: Four hundred four antiretroviral-naive patients initiating HAART at an urban HIV outpatient clinic in 1995 to 2004 were analyzed. The association of treatment responses at 3 to 9 months after HAART initiation with time to development of an opportunistic infection (OI) or death was determined using Cox proportional hazards modeling. Logistic regression modeling was used to examine the association between discordant responses and patient characteristics. RESULTS: Of 404 patients, 70.5% experienced favorable concordant responses (CD4 cell count [CD4]+/viral load [VL]+: increase in CD4 count of >or=50 cells/microL and achievement of undetectable plasma HIV RNA level), 15.8% an immunologic response only (CD4+/VL(-)), 8.7% a virologic response only (CD4(-)/VL+), and 5.0% a concordant unfavorable response (CD4(-)/VL(-)). Both types of discordant responses (CD4+/VL(-) and CD4(-)/VL+), nonresponse (CD4(-)/VL(-)), and baseline CD4 cell count were significantly associated with earlier development of an OI or death (relative hazard [RH] = 2.81, 95% confidence interval [CI]: 1.31 to 3.97; RH = 4.83, 95% CI: 2.10 to 11.12; and RH = 0.93, 95% CI: 0.88 to 0.99, respectively). CD4+/VL(-) and CD4(-)/VL(-) were associated with nonwhite race in multivariate logistic regression models (adjusted OR = 2.83, 95% CI: 1.46 to 5.47 and adjusted OR = 6.50, 95% CI: 1.65 to 25.69, respectively). CONCLUSION: Discordant immunologic and virologic responses at 3 to 9 months after HAART initiation play important roles in predicting long-term clinical outcomes in treatment-naive patients.     

Plasma levels of intact and cleaved urokinase receptor decrease in HIV-1-infected patients initiating highly active antiretroviral therapy

Elevated blood levels of soluble urokinase receptor (suPAR) measured by ELISA decrease in human immunodeficiency virus‐1 (HIV‐1)‐infected patients initiating highly active antiretroviral therapy (HAART). As the suPAR ELISA measures both three‐ and two‐domain suPAR [suPAR(I–III), suPAR(II–III)] and suPAR(I–III)–ligand complexes, the amount by which the individual suPAR forms (suPAR(I–III), suPAR(II–III) and one‐domain suPAR [suPAR(I)]) decrease in plasma in HIV‐1‐infected patients initiating HAART is unknown. Consequently, the objective of this study was to investigate HAART‐induced changes in the individual plasma suPAR forms in HIV‐1‐infected patients. Plasma suPAR was measured by three time‐resolved fluorescence immunoassays detecting suPAR(I–III), suPAR(I–III) + suPAR(II–III) and suPAR(I) in 29 treatment‐naïve HIV‐1‐infected patients followed annually for 5 years after initiation of HAART and in 20 age‐ and gender‐matched healthy individuals. In addition, plasma levels of the following inflammatory markers were also investigated: soluble tumour necrosis factor receptor (sTNFr)‐II, TNF‐α, interleukins (IL)‐10, IL‐6, IL‐4, IL‐2 and interferon (IFN)‐γ. In HIV‐1‐infected patients, plasma suPAR(I–III), suPAR(II–III) and suPAR(I) decreased within the first treatment year (all P < 0.05) and suPAR(I–III) and suPAR(II–III) remained above normal throughout follow‐up (both P < 0.05). Plasma sTNFrII, IL‐6, IFN‐γ and IL‐10 also decreased during HAART (all P < 0.05). In HIV‐1‐infected patients, sTNFrII correlated with all suPAR forms before (all P < 0.01) and after 5 years HAART (all P < 0.001), whereas sTNFrII and suPAR did not correlate in healthy individuals. Intact and cleaved plasma suPAR decreased in HIV‐1‐infected patients initiating HAART but remained above normal. The positive correlation with sTNFrII suggests that the individual plasma suPAR forms are linked to immune activation in HIV‐1 infection.     

Cost-effectiveness of alternative strategies for initiating and monitoring highly active antiretroviral therapy in the developing world

OBJECTIVE: Determine the cost-effectiveness of initiating and monitoring highly active antiretroviral therapy (HAART) in developing countries according to developing world versus developed world guidelines. DESIGN: Lifetime Markov model incorporating costs, quality of life, survival, and transmission to sexual contacts. METHODS: We evaluated treating patients with HIV in South Africa according to World Health Organization (WHO) "3 by 5" guidelines (treat CD4 counts 100,000 copies/mL, and monitor CD4 cell counts and viral load every 3 months. RESULTS: Incorporating transmission to partners (excluding indirect costs), treating patients according to developed versus developing world guidelines increased costs by US $11,867 and increased life expectancy by 3.00 quality-adjusted life-years (QALYs), for an incremental cost-effectiveness of $3956 per QALY. Including indirect costs, over the duration of the model, there are net cost savings to the economy of $39.4 billion, with increased direct medical costs of $60.5 billion offset by indirect cost savings of $99.9 billion. CONCLUSIONS: Treating patients with HIV according to developed versus developing world guidelines is highly cost-effective and may result in substantial long-term savings.     

Anemia in HIV-infected patients receiving highly active antiretroviral therapy.

BACKGROUND: Anemia is common in HIV infection, particularly in advanced disease states. We wished to determine how highly active antiretroviral therapy (HAART) and other factors affected the level of hemoglobin in HIV infection. METHODS: We analyzed data from 905 patients receiving care at Johns Hopkins in Baltimore, Maryland after July 1, 1996. Analyses were done of hemoglobin levels obtained at baseline and during 1 year of follow-up in patients who received and did not receive a HAART regimen. Use of HAART and other demographic and clinical factors were examined. RESULTS: Eleven percent of patients had a hemoglobin count <10 g/dL, 27% had a hemoglobin count 10 to 12 g/dL, and 21% had a hemoglobin count of >14 g/dL at baseline before HAART was started. During 1 year of follow-up, use of HAART was associated with a hemoglobin levels >14 g/dL in 42% of patients, irrespective of use of zidovudine as part of HAART regimen, compared with 31% of patients who did not use HAART. In multivariate analysis, use of HAART was strongly associated with not having anemia during 1 year of follow-up, adjusting for patient gender, race, injection drug use history, baseline CD4 and HIV-1 RNA levels, and anemia treatments. CONCLUSIONS: HAART is an effective treatment of the anemia of HIV infection. Patients who continue to have symptomatic anemia while receiving HAART may need additional intervention.     

Impact of highly active antiretroviral therapy on individual AIDS-defining illness incidence and survival in Australia

OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on incidence of initial AIDS-defining illnesses (ADIs) and survival after individual ADIs. METHODS: Australian AIDS notification data over the period 1993 to 2000 were examined. Analyses were based on all initial ADIs. To examine the impact of HAART, two periods of AIDS diagnosis were chosen: pre-HAART (1993-1995) and HAART (1996-2000). Comparisons between these two periods included proportion of individual ADIs, median CD4 lymphocyte counts at and survival following AIDS and individual ADIs. Median survival was based on Kaplan-Meier estimates, with examination of factors influencing survival in a Cox proportional hazards model. RESULTS: Over the period 1993 to 2000 in Australia, 5017 initial ADIs were diagnosed among 4351 AIDS cases. At AIDS diagnosis, changes from the pre-HAART (1993-1995) to HAART (1996-2000) periods included an increased proportion of Pneumocystis carinii pneumonia (PCP) (25.9% to 30.4%; p =.001), AIDS dementia complex (5.2% to 6.8%; p = 0.029), non-Hodgkin lymphoma (NHL) (4.4% to 6.3%; p =.005), and tuberculosis (0.5% to 2.7%; p <.0005). Median survival following AIDS increased from 19.6 months for AIDS cases diagnosed in 1993 to 1995 to 39.6 months for AIDS cases diagnosed in 1996 to 2000 (p <.0005). Median survival was stable for NHL (7.5-8.8 months; p =.26), but increased significantly for almost all other ADIs. CONCLUSIONS: An increased proportion of PCP relative to other ADIs suggests an increasing proportion of AIDS patients not receiving specific prophylaxis, presumably because of "late" HIV diagnosis. Survival following almost all ADIs has increased in the era of HAART, although the prognosis after NHL remains extremely poor.     

Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy

OBJECTIVE: To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality. METHODS: A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses. RESULTS: Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy. CONCLUSION: Discordant responses are independently associated with an increased risk of mortality and are, in turn, associated with poor adherence to therapy.     

Sexual dysfunction in HIV-infected patients treated with highly active antiretroviral therapy

Sexual disturbances develop in some patients treated with highly active antiretroviral therapy (HAART). To evaluate sexual dysfunction and the influence that different antiretrovirals could have on those parameters, we conducted a prospective study in patients with stable clinical condition attending an HIV outpatient clinic. A total of 351 evaluations were performed in 189 HIV-infected men, who were interviewed about symptoms of sexual dysfunction. Sexual hormones as well as other clinical and laboratory parameters were also measured at the time of each evaluation. The mean CD4 count was 451.1 x 10(6) cells/L, and viral load was undetectable in two thirds of the determinations. The prevalence of sexual dysfunction was 19.5% overall, but it was influenced by treatment, particularly (although not exclusively) by protease inhibitors (PIs) (27.1% vs. 3.8% for untreated patients). Sexual dysfunction was not related to hypophyseal or gonadal hormonal values. Although several parameters were associated with sexual dysfunction in the univariate analysis, only antiretroviral treatment was significantly predictive of this disorder in a logistic regression analysis. Sexual dysfunction is common in HIV-infected patients in stable clinical condition receiving HAART, and all antiretroviral drugs, particularly PIs, seem to be related to it. Sexual dysfunction in these patients is not related to hormonal causes.     

Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART)

Correlates of immune reconstitution after highly active antiretroviral therapy (HAART) are not completely understood, in particular as far as viro-immunological discordant responses are concerned. HIV-positive patients on stable HAART for > or = 1 year were recruited. Viro-immunological responses were categorized according to positive or negative area under the curve (AUC) variations for HIV plasma viral load (pVL) and CD4+ T-cell counts measured at least every 4 months. The following parameters were evaluated: lymphocyte spontaneous apoptosis (LSA), intracellular Bcl-2 expression in both CD4-CD45RA+ and CD4-CD45R0+, IL-7 and IL-15 plasma concentrations, and lymphocyte TRECs levels. Sixty-one patients were enrolled. A significant inverse correlation was found between CD4+ T-cell count and pVL AUC (r = 0.45; p = 0.0003). Patients with pVL response had higher levels of Bcl-2 in CD4-CD45R0+ (mean 65,409 MESF vs. 54,018 MESF; p = 0.089) and higher IL-15 (mean 1.34 pg/mL vs. 1.05 pg/mL; p = 0.069, respectively). Higher LSA and lower TRECs levels were found in viro-immunological non-responder patients with respect to those who had viro-immunological response (mean 24.84% vs. 14.89%; p = 0.01, and mean 17,796 copies/10(6) cells vs. 29,251 copies/10(6) cells; p = 0.68, respectively). Virological suppression may allow Bcl-2 and IL-15 hyperexpression during incomplete immune-reconstitution phase, while more complete immune reconstitution appeared to be marked by both high TRECs and low LSA levels, possibly indicating both central and peripheral CD4+ T-cell repopulations at this stage.     

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.