Depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy among HIV-infected persons

The association of depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy (HAART) was evaluated in 135 HIV-infected persons. Thirty percent reported nonadherence to HAART. Depressive symptoms (assessed with the Montgomery-Asberg Depression Rating Scale) and neurocognitive impairment (assessed with a neuropsychological test battery) were documented in 24% and 12%, respectively, of the study participants. Nonadherence to HAART was independently associated with worse depression rating scale scores (odds ratio=1.05, 95% confidence interval [CI]=1.00-1.10), acquisition of HIV through injection of drugs (odds ratio=2.59, 95% CI=1.05-6.39), and complaints about impairment of sexual activity (odds ratio=6.62, 95% CI=1.16-37.6). The presence of depressive symptoms, but not neurocognitive impairment, was associated with nonadherence.     

Effect of clinical pharmacists on utilization of and clinical response to antiretroviral therapy

OBJECTIVE: To determine the association of clinical pharmacists with health outcomes and utilization measures among HIV-infected patients. METHODS: Observational study of 1571 HIV-infected patients prescribed their initial highly active antiretroviral therapy (HAART) regimen in clinics with and without a clinical pharmacist. Outcomes analyzed were changes in plasma HIV RNA level, CD4 T-cell counts, and service utilization (hospital days, emergency department visits, and office visits) over 24 months based on exposure to a clinical pharmacist. RESULTS: Patients exposed to a clinical pharmacist tended to be more likely to achieve an HIV RNA level <500 copies/mL at 12 months (adjusted odds ratio [OR] = 2.01, 95% confidence interval [CI]: 0.92 to 4.37). At 24 months, however, results depended on the provider panel size; the ORs for panel sizes < or =50 and >50 HIV-infected patients were 1.67 (95% CI: 0.60 to 4.62) and 0.97 (95% CI: 0.39 to 2.41), respectively. CD4 T-cell counts were modestly but nonsignificantly higher for the patients exposed to a clinical pharmacist. Utilization also depended on the provider panel size; pharmacist exposure was associated with 64% (95% CI: 30% to 108%) and 9% (95% CI: -11% to 33%) increases in total hospital days for panel sizes < or =50 and >50 HIV-infected patients, respectively. Pharmacist exposure was also associated with a 19% (95% CI: -13% to -24%) decrease in office visits for panel sizes < or =50 HIV-infected patients, with minimal effect for larger panel sizes. CONCLUSION: Clinical pharmacists seem to contribute to lower office visit rates in antiretroviral-naive patients initiating HAART.     

Differential upregulation of CD38 on different T-cell subsets may influence the ability to reconstitute CD4+ T cells under successful highly active antiretroviral therapy

BACKGROUND: Immune activation is an independent surrogate marker of CD4 T-cell depletion in HIV-infected patients. Highly active antiretroviral therapy (HAART) reduces disease progression as a direct consequence of suppressing HIV replication. Immune function does not normalize completely in most subjects on HAART, however, perhaps reflecting residual HIV replication. So far, it is unclear to what extent immune activation may influence the evolution of CD4 T-cell counts in patients on HAART. PATIENTS AND METHODS: The expression of CD38 on naive and memory subsets of CD4+ and CD8+ T cells was measured quantitatively by flow cytometry in 62 drug-naive HIV-positive and 30 HIV-uninfected controls. In addition, the evolution of this marker as well as that of some virologic parameters (plasma viremia and proviral load) and CD4 counts were assessed in 25 HIV-infected individuals who initiated HAART and were followed for 12 months. RESULTS: The mean level of CD38 on memory CD4+ and CD8+ T cells as well as in naive CD8+ cells was significantly higher in drug-naive HIV-positive subjects than in HIV-negative controls. Moreover, it was highly correlated with viral load titers. In patients on successful HAART, immune activation declined in all T-cell subsets, particularly among memory CD8+ cells. It remained elevated with respect to HIV-negative controls, however, even after 12 months of HAART. There was a significant correlation between the CD8+ T-cell activation decay and the increase of CD4+ T cells on HAART. Patients with the highest decline in CD8 activation were those showing the highest CD4 T-cell gains after 12 months of therapy. CONCLUSIONS: The level of CD38 expression on different T-cell subsets is differentially upregulated in drug-naive HIV-infected patients. After successful HAART, immune activation decreases in all T-cell subsets, although it still remains elevated in most cases after 12 months of HAART. The extent of immune deactivation under successful HAART correlates with the ability to reconstitute CD4 counts.     

Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study

Background

Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied.

Methods

The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women’s Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence.

Results

Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load.

Conclusions

Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.

     

Why are baseline HIV RNA levels 100,000 copies/mL or greater associated with mortality after the initiation of antiretroviral therapy?

BACKGROUND: There is conflicting evidence regarding the impact of baseline plasma HIV RNA on virologic responses after the initiation of triple-drug antiretroviral therapy (highly active antiretroviral therapy [HAART]). This has made it difficult to interpret the recently reported association between baseline plasma HIV RNA and mortality. We evaluated whether baseline CD4 cell count and plasma HIV RNA predicted virologic suppression (<500 copies/mL) and rebound (> or =500 copies/mL) among adherent HIV-infected patients. METHODS: Antiretroviral-naive HIV-infected patients were stratified by baseline CD4 cell count, plasma HIV RNA, and adherence level. Cox and logistic regression were used to evaluate the time to suppression and rebound and the odds of ever achieving HIV RNA suppression. RESULTS: A total of 1422 individuals initiated HAART between August 1, 1996 and July 31, 2000 and were followed to March 31, 2002. Adherent patients with HIV RNA levels > or =100,000 copies/mL and 50 to 99,999 copies/mL were slower to suppress HIV RNA than patients with baseline HIV RNA <50,000 copies/mL in Kaplan-Meier analyses. Although the odds of RNA suppression among adherent patients with baseline RNA levels <50,000 copies/mL and 50 to 99,999 copies/mL were similar (P = 0.197), patients with baseline HIV RNA > or =100,000 copies/mL were markedly less likely ever to achieve suppression during follow-up (adjusted odds ratio: 0.27 [95% confidence interval: 0.13-0.54]; P < 0.001). No differences in the rate of virologic rebound were observed between adherent patients in the various baseline HIV RNA strata, and CD4 cell count was not associated with suppression or rebound. CONCLUSIONS: Baseline HIV RNA > or =100,000 copies/mL was associated with a significantly lower likelihood of ever achieving HIV RNA suppression during follow-up. These findings likely explain the association between baseline HIV RNA levels and mortality and have important implications for the development of therapeutic guidelines.     

Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS cohort study

OBJECTIVE: Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men. METHODS: Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as > or =1 log10 copies/mL across the visit pairs. RESULT:: Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with < or =1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for < or =7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts. CONCLUSIONS: Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.     

Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses

Human immunodeficiency virus (HIV) infection leads to severe CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) that persists despite the initiation of highly active antiretroviral therapy (HAART). It is not known whether restoration of gut mucosal CD4+ T cells and their functions is feasible during therapy and how that relates to immune correlates and viral reservoirs. Intestinal biopsies and peripheral blood samples from HIV-infected patients who were either HAART naive or on long-term HAART were evaluated. Our data demonstrated that gut CD4+ T-cell restoration ranged from modest (<50%) to high (>50%), compared with uninfected controls. Despite persistent CD4+ T-cell proviral burden and residual immune activation in GALT during HAART, effective CD4+ T-cell restoration (>50%) was achieved, which was associated with enhanced Th17 CD4+ T-cell accumulation and polyfunctional anti-HIV cellular responses. Our findings suggest that a threshold of>50% CD4+ T-cell restoration may be sufficient for polyfunctional HIV-specific T cells with implications in the evaluation of vaccines and therapeutics.     

TTV Viral Load As a Marker for Immune Reconstitution After Initiation of HAART in HIV-Infected Patients

Abstract

Purpose: To investigate whether TT virus (TTV) viral load may be used as a surrogate marker for functional immune reconstitution in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Method: Fifteen protease inhibitor-naÏve HIV-infected patients were included in a longitudinal study. From each patient, three serum samples taken before HAART initiation and three samples taken during HAART were analyzed. TTV was detected by polymerase chain reaction (PCR) and was quantitated by competitive PCR. TTV viral heterogeneity was determined by restriction fragment length polymorphisms (RFLPs) and sequencing. Results: All 15 HIV-infected patients were TTV positive. No significant change in HIV RNA or TTV viral load was observed at the three time points before HAART initiation. Even though HAART lead to an immediate and significant reduction in HIV RNA (p = .0001), a significant reduction in TTV viral load (p = .0002) was not observed until after 3-5 months of HAART. Four patients did not have an increase in CD4+ T cell count after 1 year of HAART; however, a decrease in TTV viral load was still observed, and three of these patients had a reduction in HIV RNA. RFLPs and sequencing revealed that TTV is represented as a heterogeneous population of virus in HIV-infected patients. Conclusion: This pilot study suggests that HAART leads to improved immunological responses, even in patients who do not have an increase in CD4+ T cell counts. We propose that the change in TTV viral load may be useful in the evaluation of cellular immune response at a functional level in HIV-infected patients who receive HAART.     

Highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: analysis of cellular immune responses

The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4+ T-cell counts, plasma HIV RNA levels, and the delayed-type hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4+ T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4+ T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART.     

HIV and the breast

HIV infection and antiretroviral therapy may alter the spectrum and frequency of diseases that affect the breast. The differential diagnosis of conditions of the breast that a practitioner may encounter in HIV-infected persons includes infection, morphologic alterations, and malignancy. Atypical infections may involve the breast as CD4+ T-cell counts wane. More commonly, HIV-infected persons present with gynecomastia, which may be caused by a variety of conditions, including exposure to HAART. True gynecomastia, resulting from proliferation of male breast ducts and periductal stroma, might be differentiated from lipomastia--a manifestation of lipodystrophy, characterized by the deposition of adipose tissue in the breast. In the era of HAART, HIV-infected patients with malignancy--particularly those who have robust CD4+ T-cell counts and well-controlled HIV viral loads--should be treated similarly to their HIV-negative counterparts.     

Antidepressant treatment improves adherence to antiretroviral therapy among depressed HIV-infected patients

BACKGROUND: Antiretroviral regimens for HIV-infected patients require strict adherence. Untreated depression has been associated with medication nonadherence. We proposed to evaluate the effect of antidepressant treatment (ADT) on antiretroviral adherence. METHODS: Data were retrieved for HIV-infected patients seen at an urban health care setting (1997-2001) from chart review and administrative and pharmacy files. Antiretroviral adherence was determined for depressed patients stratified by receipt of and adherence to ADT. Antiretroviral adherence was compared before and after initiation of ADT. RESULTS: Of 1713 HIV-infected patients, 57% were depressed; of those, 46% and 52% received ADT and antiretroviral treatment, respectively. Antiretroviral adherence was lower among depressed patients not on ADT (vs. those on ADT; P = 0.012). Adherence to antiretroviral treatment was higher among patients adherent to ADT (vs. those nonadherent to antidepressant treatment; P = 0.0014). Antiretroviral adherence improved over a 6-month period for adherent, nonadherent, and nonprescribed ADT groups; however, the mean pre- versus post-6-month change in antiretroviral adherence was significantly greater for those prescribed antidepressants. CONCLUSIONS: Depression was common, and antiretroviral adherence was higher for depressed patients prescribed and adherent to ADT compared with those neither prescribed nor adherent to ADT. Attention to diagnosis and treatment of depressive disorders in this population may improve antiretroviral adherence and ultimate survival.     

Control of HIV-1 RNA load after HAART interruption: relationship with CCR5 co-receptor density and proviral DNA load in HIV-infected patients.

BACKGROUND: CCR5 co-receptor density has been reported to play a role in the level of HIV production. In addition, reports about the relationship between proviral DNA load and plasma HIV load are controversial. OBJECTIVES: To analyse the role of CCR5 co-receptor density and proviral DNA load in the control of plasma HIV-viral load after HAART interruption, comparing patients whose plasma HIV load was persistently below 4log(10) RNA copies/mL, defined as "HIV controllers", with patients who showed a viral load higher than 4log(10) RNA copies/mL, defined as "non-controllers". STUDY DESIGN: Proviral DNA load quantification (N=55) and CCR5 co-receptor density (N=29) were determined in HIV-infected patients on prolonged HAART interruption. RESULTS: Twenty-three percent of our HAART interruption cohort were classified as HIV controllers, while 77% were classified as non-controllers. CCR5 co-receptor density was statistically higher in HIV controllers than in non-controllers, while proviral DNA load was not different between them. CCR5 co-receptor density in activated CD4 cells was independently associated with HIV plasma load after interruption. CONCLUSIONS: The observation of a higher CCR5 co-receptor expression in HIV controllers suggests that HIV infection leads to the selection of CD4 cells with low CCR5 co-receptor density after HAART interruption.     

Use of highly active antiretroviral therapy in HIV-infected women: impact of HIV specialist care.

OBJECTIVES: To evaluate factors associated with use of HIV specialist care by women, and to determine whether medical indications for therapy validate lower rates of antiretroviral use in women not using HIV specialty care. DESIGN: Cross-sectional analysis of the 1998 interview from the HIV Epidemiology Research Study (HERS) cohort. METHODS: Data from 273 HIV-infected women in the HERS were analyzed by multiple logistic regression to calculate predictors of the use of HIV specialist care providers. Variables included study site, age, education, insurance status, income, substance abuse, depression, AIDS diagnosis, CD4 + lymphocyte count, and HIV-1 viral load. In addition, medical indications for therapy and medical advice to begin antiretroviral therapy were assessed. RESULTS: Of 273 women, 222 (81%) used HIV specialists and 51 (19%) did not. Having health insurance, not being an injection drug user, and being depressed were predictive of using HIV specialist care (all p < or = .05). Although medical indications for therapy in the two groups were comparable, the rate of highly active antiretroviral therapy (HAART) use was significantly higher in women using HIV specialist care (27%) compared with those not using HIV specialists (7.8%). Women using HIV specialists received significantly more advice to begin antiretroviral therapy (ART) in the 6 months prior to the interview compared with those not using specialists (relative risk, 2.4; 95% CI = 1.3-4.6). CONCLUSIONS: Having insurance, not being an injection drug user, and being depressed all increased the likelihood of women receiving HIV specialty care, which, in turn, increased the likelihood of receiving recommended therapies. The level of HAART use (23%) and any ART use (47%) in these HIV-infected women was disturbingly low. Despite comparable medical indications, fewer women obtaining care from other than HIV specialists received HAART. These data indicate substantial gaps in access to HIV specialist care and thereby to currently recommended antiretroviral treatment.     

Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in children with human immunodeficiency virus undergoing highly active antiretroviral therapy.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (23PSV) has been recommended for children infected with human immunodeficiency virus (HIV); however, the efficacy of this vaccination in HIV-infected children undergoing highly active antiretroviral therapy (HAART) has not been studied. OBJECTIVE: To study the immunogenicity and immunologic protection of 23PSV in HIV-infected children after stable HAART. METHODS: Serotype-specific IgG antibodies to 12 pneumococcal capsular polysaccharides were analyzed before and after 23PSV vaccination in 41 HIV-infected children undergoing HAART and compared with 95 HIV-negative control children. Seropositivity, clinical protection, and additional clinical protection from 23PSV were calculated based on serotype specific IgG antibody levels and on the known incidence of these serotypes for causing invasive disease. RESULTS: Children with HIV infection undergoing HAART developed a significant increase in specific IgG levels to Streptococcus pneumoniae after 23PSV vaccination (0.95 vs 1.84 micro/gmL, P < .001). The HIV-infected children with CD4+ cell counts of 25% or higher at the time of vaccination developed a higher additional clinical protection gain from 23PSV vaccination than did children with a lower percentage of CD4+ cells. CONCLUSIONS: HIV-infected children undergoing stable HAART develop a significant immunologic response to 23PSV, especially those with higher T-cell counts and lower viral loads at the time of vaccination.     

Antiretroviral adherence and use of alternative therapies among older HIV-infected adults

OBJECTIVE: To investigate adherence to antiretroviral therapy and use of alternative therapies among older human immunodeficiency virus (HIV)-infected adults, and to assess relationships between antiretroviral adherence and clinical outcomes. METHODS: One hundred older HIV-infected patients, aged 50 and over, treated at two large HIV clinics in Washington, DC, were enrolled. A cross-sectional methodology used structured interviews to investigate antiretroviral regimens, use of alternative therapies, and demographics. Medical records provided viral load and CD4 count within 3 months of interview. RESULTS: The mean self-reported adherence was 94%, and 55 patients reported 100% adherence to antiretroviral therapy. Correlation analysis showed a significant negative correlation between adherence and viral load (r = -312, p = 0.005). There was no significant difference in adherence based on race, gender, mode of transmission, or education. Twenty-one patients (21%) reported the use of an alternative therapy, with several patients using multiple alternative therapies. There was no significant difference in adherence score (p = 0.514) or viral load (p = 0.860) based upon use of alternative therapies. CONCLUSIONS: Older HIV-infected study patients reported high levels of adherence to antiretroviral regimens, and adherence was highly correlated with HIV viral load. Use of alternative therapies did not significantly impact adherence to antiretroviral agents or viral load. High adherence among this older population may be related to older patients' familiarity with medication usage, their increasing awareness of HIV as a disease that requires optimal adherence, and educational efforts promoted by the two clinics in which they are clients.     

Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: Analysis of Cellular Immune Responses

The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4⁺ T-cell counts, plasma HIV RNA levels, and the delayed-type hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4⁺ T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4⁺ T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART.     

The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

This study investigated the effect of resistance testing quantified through a genotypic sensitivity score (GSS) on virologic, immunologic, and clinical responses among patients with late stage HIV‐1 disease receiving supervised highly active antiretroviral therapy (HAART). Newly admitted patients received drug resistance testing (n = 198) and then HAART supervised by residential health‐care facilities nurses. After initiating a resistance testing‐informed HAART regimen, patients were followed for HIV‐1 RNA suppression (<50 copies/ml), mean change in CD4⁺ T‐cells, new AIDS defining category C opportunistic conditions and death. GSS was constructed using the HAART regimen prescribed after resistance testing and data derived from IAS‐USA consensus mutations table with modification. Regressions with generalized estimating equations for robust estimation of standard errors and Cox proportional hazards regression estimated independent associations between GSS and treatment responses. After adjusting for adherence, initial log₁₀ HIV‐1 RNA levels, and other covariates, patients with a GSS ≥3 had significantly greater HIV‐1 RNA suppression (adjusted odds ratio (AOR) 2.32; 95% CI 1.14, 4.75). HIV‐1 RNA levels were lower among patients with ≥95% adherence, but the effect of GSS on viral suppression was not modified by adherence. Self‐rated health status, and baseline CD4⁺ T‐cell counts independently predicted HIV‐1 RNA suppression. GSS did not predict mean change in CD4⁺ cells/mm³ (236 vs. 233, P = 0.92), occurrence of new AIDS defining category C conditions or death. These data support resistance testing‐guided therapy as an independent predictive factor to improve virologic responses in treatment‐experienced patients. J. Med. Virol. 81:1323–1335, 2009. © 2009 Wiley‐Liss, Inc.     

CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater

OBJECTIVE: CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort. METHODS: Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients. RESULTS: Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration. CONCLUSIONS: Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend.     

Normalized CD8+ but not CD4+ lymphocyte IL-2 expression is associated with early treatment with highly active antiretroviral therapy

CD4+ and CD8+ lymphocyte cytokine production in patients with HIV/AIDS and Controls, in response to stimulation with phorbol-12-myristate-13-acetate (PMA) and ionomycin was assessed using single cell flow cytometric methods. Sixty-eight patients with HIV were divided into those on no antiretroviral therapy and those on highly active antiretroviral therapy (HAART). Patients on HAART were analyzed further on the basis of gender, ethnicity, viral load (> or 100 or <100 cells/mm(3)) and CD4 count (>200 or <200 cells/mm(3)). Interferon gamma (IFNgamma) expression by CD4+ and CD8+ lymphocytes was elevated in HIV-infected groups as compared to Controls. This elevation was statistically significant for patients on HAART but not for those not on HAART. The most significant difference was seen when the CD4+ count reached >200 cells/mm(3) (p=0.018 for CD4+ IFNgamma production and p=0.004 for CD8+ IFNgamma production). CD4+ interleukin-2 (IL-2) expression was significantly lower in HIV patients as compared to Controls but did not significantly improve however good the response to HAART. IL-2 expression by CD8+ lymphocytes was also lower in HIV patients as compared to Controls. IL-2 expression by CD8+ lymphocytes significantly improved in all patients on HAART as compared to HIV patients on no HAART. IL-2 expression was not significantly different from that of the Controls when the HIV viral load was less than 50 copies/ml. These results demonstrate improvements in both CD4+ and CD8+ responsiveness with HAART. IFNgamma production was elevated in response to HAART and was maximal only with significant CD4 count recovery. In contrast, normalization of IL-2 production by CD8+ lymphocytes was seen early in patients receiving HAART even when there was only a small increase in CD4+ lymphocyte numbers.