HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population

OBJECTIVE: To compare mortality rates in combination antiretroviral therapy (cART)-treated HIV-infected adults with mortality in the general population according to the level of CD4 cell count reached and the duration of exposure to cART. METHODS: HIV-infected adults initiating a protease inhibitor-containing treatment between 1997 and 1999 were selected in the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS) APROCO and AQUITAINE cohorts. CD4 cell counts were estimated during follow-up using a 2-phase mixed linear model. Standardized mortality ratios (SMRs) were computed in reference to the 2002 French population rates, overall and for the time period spent with a CD4 count >or=500 cells/mm3. To identify if and when mortality rates reached values of the general population, SMRs were computed successively with truncation at each year of follow-up. RESULTS: The 2,435 adults (77% men, baseline median age = 36 years, and baseline median CD4 count = 270 cells/mm3) had a median follow-up of 6.8 years. The SMR was 7.0 (95% confidence interval [CI]: 6.2 to 7.8). During the 5,402 person-years spent with a CD4 count >or=500 cells/mm3, the mortality reached the level of the general population after the sixth year after cART initiation (SMR = 0.5, 95% CI: 0.1 to 1.6). CONCLUSION: Although overall mortality was higher in cART-treated HIV-infected adults, a subgroup with especially good prognosis can be identified, and these characteristics should be targeted for long-term treatment.     

Changes in outcome of persons initiating highly active antiretroviral therapy at a CD4 count less than 50 Cells/mm3

BACKGROUND: Although HIV treatment guidelines recommend highly active antiretroviral therapy (HAART) initiation before reaching a CD4 count of 200 cells/mm3, many people in resource-rich settings, and a substantial proportion in resource-limited settings, present at levels <50 cells/mm3. METHODS: Using UK Collaborative HIV Cohort data, we assessed virologic response to HAART for antiretroviral-naive persons initiating therapy at a CD4 count <50 cells/mm3. We also investigated changes in the probability of having a viral level <400 copies/mL at 48 weeks over calendar time adjusting for gender, age, exposure category, ethnicity, baseline CD4 count and viral load, and whether the regimen contained a protease inhibitor. RESULTS: At 12, 24, 36, and 48 weeks, 80%, 83%, 85%, and 83% of participants, respectively, had a viral level <400 copies/mL. This proportion rose from 1997 to 1998, falling slightly in the most recent calendar period. By far the most important predictor of virologic suppression was calendar year of starting HAART (odds ratio [OR] = 2.49, 4.28, and 3.28 for 1999 to 2000, 2001 to 2002, and 2003 to 2005, respectively, compared with 1997 to 1998). Women were more likely to have a viral level <400 copies/mL at week 48 compared with men (OR = 1.74, 95% confidence interval [CI]: 1.07 to 3.02), as were older individuals (OR = 1.46, 95% CI: 1.11 to 1.96 for every 10 years older). There was marginal or no evidence that other factors were associated with outcome. The estimated corresponding probabilities of achieving a viral level <50 copies/mL at week 48 were 71%, 75%, and 79% for a woman aged 25, 35, and 45 years, respectively, initiating HAART in the most recent calendar period. The respective probabilities for a man at those ages were 68%, 73%, and 78%. CONCLUSIONS: These data, albeit under conditions of good infrastructure for care delivery, are a useful comparator for other populations starting therapy at similar levels of immunodeficiency and may be valuable for evaluating the success of antiretroviral therapy rollout programs.     

Natural evolution of CD4+ cell count in patients with CD4 >350 or >500 cells/mm3 at the time of diagnosis according to HIV‐1 coreceptor tropism

The HIV‐1 coreceptor usage may play a critical role in AIDS pathogenesis and the X4‐using viruses are considered to be more pathogenic than the R5‐tropic viruses. These observations may influence the therapeutic decisions by asking for an earlier antiretroviral (ARV) treatment for the patients infected by the X4‐tropic viruses compared with those infected by the R5‐tropic viruses. The natural evolution of CD4+ cell count for 109 non‐treated patients infected by the R5‐ or X4‐tropic HIV‐1 viruses with CD4+ >350 and >500 cells/mm³ at time of diagnosis was compared until the initiation of an ARV regimen. The coreceptor usage was determined from the V3 env region sequence by Geno2Pheno (false positive rate 10%). A mixed linear regression model to analyse the CD4+ data with tropism as fixed effect in the model was used. Overall, 93 (85.3%) and 16 (14.7%) were infected by R5‐ and X4‐tropic viruses, respectively. The median age, baseline CD4+ cell count, and viral load were 34 years (IQR: 30–42), 523 cells/mm³ (IQR: 420–604), and 4.5 log₁₀ copies/ml (IQR: 3.9–5.0), respectively. There was no statistical difference in time to progression between the patients harboring R5‐ or X4‐tropic viruses. The same results were observed for the sub‐group of patients with CD4+ cell count >500 cells/mm³. The virus tropism has no impact on the CD4+ cell count evolution in these HIV‐1 patients diagnosed with CD4+ >350 or >500 cells/mm³ suggesting that the tropism determination at time of diagnosis does not seem to be a useful tool to predict the clinical progression. J. Med. Virol. 84:1853–1856, 2012. © 2012 Wiley Periodicals, Inc.     

Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.     

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.     

Effect of an oral therapeutic HIV-1 vaccine on AIDS patients with CD4 count above 250 cells/mm3

A simple delivery route, e.g. oral, would greatly facilitate the acceptance of an AIDS vaccine by a large target population. We developed a vaccine that took advantage of inherent properties of mucosal immunity in response to oral antigen challenge, namely the V-1 Immunitor vaccine (V1), which is a polyvalent oral Human immunodeficiency virus 1 (HIV-1) vaccine. The vaccine, currently manufactured in Thailand, contains pooled, inactivated viral antigens. In order to compare this vaccine with HIV-1 therapeutic vaccines reported earlier we analyzed retrospectively 13 HIV-1-positive patients that had the baseline CD4 T-cell counts greater than 250 cells/mm3 (range 270-605 cells/mm3). The patients self-administered one 850 mg vaccine tablet at breakfast and dinnertime for an average of 32 weeks (median 26 weeks). The treatment was well tolerated without any toxic effect. Twelve of thirteen patients (92%) and 9 of 13 patients (69%) experienced an elevation in CD4 and CD8 cells. The mean increase in absolute CD4 and CD8 cell counts across this group was 98 (22%; P = 0.02) and 324 (26%; P = 0.05) cells/mm3, respectively. Viral plasma load was measured by PCR in six patients. The observed viremia reduction was within 1 log unit. Subjective parameters, i.e., appetite, energy, and sense of well-being were reported by patients as being markedly improved, reflected in a mean body weight gain of 2.75 kg (P = 0.0008). Oral administration of HIV-1 immunogens provides compelling clinical response, especially when patients are treated earlier.     

Initiation of antiretroviral therapy at CD4 cell counts >/=350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency

BACKGROUND: US guidelines recommend deferring initiation of highly active antiretroviral therapy (HAART) for most patients with CD4 counts >350 cells/mm in part because of concerns about antiretroviral toxicity. METHODS: Incidence rates of peripheral neuropathy, anemia, and renal insufficiency in a cohort of 2165 patients followed more than 3 years (mean) were analyzed in multivariate Cox proportional hazards models by CD4 cell counts at initiation of HAART. A nested cohort of 895 patients restricted to study participants who did or did not start HAART within a CD4 cell count stratum were also compared. RESULTS: Incidence and risks of all 3 comorbidities decreased with initiation of HAART at CD4 counts >200 cells/mm versus <200 cells/mm. Incidence and risks of renal insufficiency were similar with HAART initiation at CD4 counts >/=350 cells/mm versus 200 to 349 cells/mm, but risk of peripheral neuropathy and anemia were further decreased in persons starting HAART at a CD4 count >/=350 cells/mm. The incidence of these conditions was highest during the first 6 months of treatment at any CD4 cell count and declined up to 19-fold with further therapy. DISCUSSION: Initiating HAART at CD4 cell counts >/=200 cells/mm reduced the incidence and risk of the 3 comorbid conditions and for anemia and peripheral neuropathy as well by starting at CD4 counts >/=350 cells/mm. The incidence of each condition decreased rapidly and remained low with increasing time on HAART.     

Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count

Current treatment guidelines for HIV infection recommend a relatively late initiation of highly active antiretroviral therapy (HAART). Nevertheless, there is still a concern that immune recovery may not be as complete once CD4+ T cells have decreased below a certain threshold. This study addressed the long-term response of CD4+ T-cell counts in patients on HAART and analyzed the influence of baseline CD4+ T-cell counts, baseline viral load, and age. An observational analysis of evolution of CD4+ T cells in 861 antiretroviral therapy-naive chronic HIV-1-infected patients who started treatment consisting of at least 3 drugs in or after 1996 was performed. Patients were classified in 4 groups according to baseline CD4+ T cells: <200 cells/mm3, 200-349 cells/mm3, 350-499 cells/mm3, and >or=500 cells/mm3. The main outcome measures were proportion of patients with CD4+ T cells <200/mm3 and >500/mm3 at last determination and rate of CD4+ T-cell recovery. Patients were followed-up for a median of 173 weeks (interquartile range [IQR], 100-234). There were no differences in follow-up between the 4 groups. CD4+ T cells increased in the whole cohort from a median of 214 cells/mm3 (IQR, 90-355) to 499 cells/mm3 (IQR, 312-733) (P<0.001). Compared with the group with a baseline CD4+ T-cell count of >or=500/mm3, the relative risk of having a last determination of CD4+ T-cell counts >200 cells/mm3 was 0.79 (95% CI, 0.75-0.83), 0.92 (95% CI, 0.89-0.96) and 1 for baseline CD4+ T cells <200 cells/mm3, 200-349 cells/mm3, and 350-499 cells/mm3, respectively. The relative risk of having a last determination of CD4+ T-cell counts >500 cells/mm3 was 0.32 (95% CI, 0.27-0.39, P<0.001), 0.69 (95% CI, 0.60-0.79, P<0.001), and 0.94 (95% CI, 0.83-1.06, P=0.38) for baseline CD4+ T-cell counts <200 cells/mm3, 200-349 cells/mm3, and 350-0499 cells/mm3, respectively, compared with a baseline CD4+ T-cell count of >or=500 cells/mm3. The increase in CD4+ T cells from baseline was statistically significant and was maintained for up to 4 years of follow-up. This increase seemed to slow down after approximately 3 years and reached a plateau after 4-5 years of follow-up even in patients who achieved and maintained viral suppression in plasma. Long-term immune recovery is possible regardless of baseline CD4+ T-cell count. However, patients who start therapy with a CD4+ T-cell count <200 cells/mm3 have poorer immunologic outcome as measured by the proportion of patients with CD4+ T cells <200/mm3 or >500/mm3 at last determination. It seems that the immune recovery slows down after approximately 3 years of HAART and reaches a plateau after 4-5 years of HAART.     

No effect of interleukin-2 on IgE levels given in addition to antiretroviral therapy in HIV-infected adults with CD4 >300 cells/mm3

HIV-infected patients may have frequent atopy caused by an imbalance of Th1 and Th2 cytokines. The objective of the present study was to investigate whether IL-2 given in addition to antiretrovirals (ARV) would result in lower IgE levels and less allergic symptoms. Patients naive to IL-2 (n=28) began IL-2 plus ARV and were followed for 12 months. IgE, eosinophil and CD4 counts, HIV RNA, symptom scoring, PFT and skin prick test (SPT) were performed. It was found that the baseline median CD4 and IgE were 386.5 cells/mm3 and 63.5 IU/ml, respectively. Four patients had allergic rhinitis (AR) and 61% had a positive SPT to at least 1 antigen. At month 12, patients had higher CD4 counts (p < 0.001) compared to the baseline; however, there were no differences in IgE levels, allergic symptom scores or HIV RNA. The eosinophil count was higher after IL-2 administration. It was concluded that IL-2 plus ARV resulted in higher CD4 counts but had no effect on atopy.     

Alternatives to HIV-RNA and CD4 count to monitor HIV disease progression: a prospective cohort study in Romania

Little evidence exists on how to efficiently and effectively monitor HIV-disease progression in developing countries. Better understanding regarding cost-effective tests may help to resolve questions regarding treatment. A prospective cohort study was conducted with a 1-year follow-up period. Immune complex-dissociated (ICD) p24 antigen (ICD p24Ag), alone or in combination with HIV p24 antibody (p24Ab), was compared to HIV-RNA and CD4+ count in a cohort of 160 HIV-infected adolescents in Romania. The main outcome measure was disease progression, defined as >50,000 copies/ml of HIV-RNA or death. Among the 160 adolescents, a higher mean ICD p24Ag was significantly associated with clinical disease classification (CDC), plasma HIV-RNA concentration, and p24Ab. Multivariate logistic regression showed detectable ICD p24Ag had an odds ratio of 3.7 (95% CI 1.4-9.7) for disease progression in comparison to undetectable ICD p24Ag. ICD p24Ag is of value in determining the prognosis of disease in HIV-1-infected adolescents in developing countries. Additional studies for validation of this assay for HIV clades primarily affecting developing countries, are now needed.     

Mannose-binding lectin in HIV infection: relation to disease progression and highly active antiretroviral therapy

To gain insight into the possible role of mannose-binding lectin (MBL) in HIV infection, we analyzed serum levels and the functional complement activation capacity of MBL in different clinical stages of HIV infection during cross-sectional analysis (n = 62) and longitudinal testing (n = 23) as well as during highly active antiretroviral therapy (HAART) (n = 40). The results were correlated with serum levels of C-reactive protein (CRP). Our main findings were as follows. MBL levels and the capacity of complement activation by the MBL pathway were increased in HIV-infected patients with advanced clinical disease as shown in both cross-sectional analysis and longitudinal testing. There was no "normalization" of these parameters during HAART. In fact, MBL levels increased during therapy, and this increase was associated with a good virologic response. Although both MBL and CRP are regarded as acute-phase proteins, no correlation was seen between these proteins. Thus, the notably diverse patterns of MBL responses among patients with different clinical courses and treatments suggest that MBL and complement activation by the MBL pathway could be involved in the pathophysiology of HIV infection. It is not inconceivable that the net effects of MBL responses may vary in different clinical settings.     

Baseline CD4 cell count and outcome of pegylated interferon plus ribavirin therapy in HIV/hepatitis C virus-coinfected patients

OBJECTIVE: When to start hepatitis C treatment in HIV/hepatitis C virus (HCV)-coinfected patients remains unresolved. Our objective was to determine if a baseline CD4 count >/=350 cells/mm predicts a sustained HCV response to pegylated interferon plus ribavirin. METHODS: We conducted a multicenter cohort study of HIV/HCV-coinfected patients treated for HIV in hospitals in Nice, Tourcoing, and Marseille (France). Sustained viral response (SVR) was defined as undetectable HCV RNA 24 weeks after treatment. The relation between CD4 cell count and SVR was examined separately for patients with HCV genotype 1 or non-1. RESULTS: One hundred seventy-five patients were included. In patients with HCV genotype 1, the rate of SVR was 13% and was not related to baseline CD4 cell count (odds ratio [OR] = 1.0, 95% confidence interval [CI]: 0.1 to 9.3). In patients with HCV genotype non-1, the rate of SVR was 46% and was not significantly increased by a baseline CD4 count >/=350 cells/mm (OR = 1.8, 95% CI: 0.6 to 5.9). CONCLUSIONS: Higher CD4 cell count at treatment initiation with pegylated interferon plus ribavirin did not improve treatment success probability, regardless of HCV genotype.     

The number and function of circulating dendritic cells may limit effector memory CD4+ T-cell responses in HIV patients responding to antiretroviral therapy

Some HIV patients who previously experienced severe immunodeficiency retain low pathogen-specific T-cell responses despite a virological response to antiretroviral therapy (ART). To identify correlates with dysfunction in accessory cell populations, HIV patients were stratified into groups maintaining high or low CD4⁺ T-cell IFN-γ responses to cytomegalovirus (CMV) over 4–8 years on ART. Myeloid dendritic cells (mDC), plasmacytoid (p) DC, M-DC8⁺ cells and monocytes were enumerated and mRNA of cytokines and activation molecules were quantitated in purified subpopulations. Proportions of pDC were lower (p = 0.043) and mDC were higher (p = 0.043) in low responders. TRAIL receptor 2 (DR5) mRNA levels in pDC (p = 0.0008) and mDC (p = 0.0062) were lower in high responders compared to controls. Levels of IL-15 mRNA were higher in mDC from high responders (p = 0.015) and levels of IL-10 mRNA were higher in M-DC8⁺ cells from low responders (p = 0.036). Hence CMV-specific CD4⁺ T-cell IFN-γ responses may be affected by numbers and function of circulating DC.     

HIV pathogenesis: gp120-antibody complexes bind CD4 and kill T4 cells--immunotoxin therapy should prevent the progression of HIV to AIDS.

Current models of the role of human immunodeficiency virus (HIV) in the pathogenesis of acquired immune deficiency syndrome (AIDS) are inadequate and inconsistent with the literature. This article reviews a wide range of AIDS research and proposes the first model of HIV pathogenesis that is entirely consistent with the literature. This model is based on antibody-gp120 complex crosslinking of CD4 on the T4 cells. Previously unexplained observations embraced by this model include early qualitative defects in the immune system, changes in cytokine expression, 'bystander' T4 cell death, and the apparent discrepancy between the low rate of T4 cell infection and the near-complete elimination of T4 cells in AIDS. A new class of drugs based on this model is detailed. These drugs should disrupt the pathway leading to AIDS and leave an HIV infection indefinitely asymptomatic. These drugs are designed to be readily modified, so the treatment is immune to HIV's notorious mutation-based drug resistance.     

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.     

Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study

OBJECTIVES: To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy. METHODS: In this study, 525 mostly chronically infected EuroSIDA patients were included who had genotypic resistance tests performed on plasma samples collected while antiretroviral therapy naive. TDR was defined as at least one resistance mutation from a list proposed for genotypic TDR surveillance. Multivariable logistic regression was used to analyze factors associated with detection of TDR, with virological (viral load<500 copies/mL) and CD4 count response (>or=50% increase) to combination antiretroviral therapy at months 6-12. RESULTS: The overall prevalence of TDR was 11.4%, which was stable over 1996-2004. There were no significant differences in virological suppression (those resistant to at least one drug prescribed versus susceptible), adjusted odds ratio: 0.68 (95% confidence interval: 0.27 to 1.71; P=0.408) or CD4 count response, adjusted odds ratio: 1.65 (95% confidence interval: 0.73 to 3.73; P=0.231). CONCLUSIONS: Prevalence of TDR in antiretroviral-naive patients was found to be in line with other European studies. No significant differences were found in virological and CD4 count response after initiation of first-line combination antiretroviral therapy between resistant and susceptible patients, possibly due to the small number of patients with resistance and consequently low power.