Clinical, biologic, and behavioral predictors of early immunologic and virologic response in HIV-infected patients initiating protease inhibitors

Predictors of virologic (plasma HIV RNA viral load [VL] < 500 copies/ml) and immunologic (rise in CD4+ cell count > 50 cells/mm3) response after 4 months of therapy (M4) were studied in 750 HIV-1-infected patients prospectively enrolled at the initiation of a protease inhibitor (PI)-containing regimen. A virologic response was observed in 80% of patients, and an immunologic response was observed in 64%. Sixty-two percent of patients self-reported full adherence to therapy at 1 month of therapy (M1) and M4. In multivariate analysis, a virologic response was more frequent in fully adherent patients (odds ratio [OR] = 2.0; p =.001). An immunologic response was associated with age < 36 years (OR =1.4; p =.03), baseline VL (OR = 1.5 per 1 log10 copies/ml higher; p <.01), decrease in VL at M1 (OR = 1.5 per 1 log10 copies/ml decrease; p <.01), baseline total lymphocyte count (OR = 1.7 per 50% lower; p <.001), and baseline CD4+ cell percentage > or = 20% (OR =1.9; p <.001) but not with adherence to therapy. Full adherence seems to be a major predictor of a virologic response to PI-containing triple therapy. An immunologic response may be possible despite incomplete adherence, at least early in therapy.     

Predictors of virologic response to ritonavir-boosted protease inhibitors

The primary mechanism of resistance to protease inhibitors involves the stepwise accumulation of mutations that alter and block the substrate binding site of HIV protease. The large degree of cross-resistance among the different protease inhibitors is a source of considerable concern for the management of patients after treatment failure. Although the output of HIV-resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virologic outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However, the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and the analytical methodology used to derive it. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. Combining the information of therapeutic drug monitoring and resistance tests is likely to be of greatest clinical utility in antiretroviral-experienced patients harboring HIV strains with reduced susceptibility. The combination of pharmacologic and virologic parameters as a predictor of the virologic response has been merged into the parameter known as "inhibitory quotient". This article discusses the potential interest of the use of inhibitory quotients as an approach for enhancing the potency and durability of boosted protease inhibitors against protease inhibitor-resistant viruses.     

Iron deficiency anemia in HIV infection: immunologic and virologic response

We report the immunologic and virologic response of iron deficiency anemia in two cases of human immunodeficiency virus (HIV)-infected individuals. The findings of this report suggest that caution be exercised in prescribing iron supplements to HIV-infected patients. The treatment of iron deficiency anemia should be combined with antiretroviral agents in people living with HIV/AIDS to avoid adverse immunologic and virologic consequences.     

Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study

Objectives:

Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care.

Methods:

We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007–2011.We identified patients who started (baseline date) either continuous ≥?30?days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan–Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA ??3 during follow-up.

Results:

Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205?cells?mm^??3; mean baseline CD4, 460?cells?mm^??3; HIV RNA ??1 in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3?years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA ??1 (P?=?0.51); 69 and 58%, respectively, achieved a CD4 increase ≥?50?cells?mm^??3 (P?=?0.70).

Discussion:

In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART.     

Long-term clinical,immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection

Background  

To test the hypothesis of down-regulating the increased immune system activation/destruction process associated with chronic HIV infection, we focused our interest on prednisolone (PDN), because we had showed that, in vitro, PDN had a strong anti-apoptotic activity on activated T cells of HIV-infected patients and no effect on viral replication. We thus designed in 1992 a pilot study to evaluate the clinical, immunologic and virologic effects of PDN. The drug was given to a group of 44 patients with CD4 T cells over 200/μl. After one year, no patient had developed clinical AIDS and the mean CD4 T cell count of the group had increased from 441 ± 21 cells/μl to 553 ± 43 cells/μl. Moreover, markers of immune activation had dropped back to normal levels while the mean viral load of the group had remained unchanged. Here we explore the long-term clinical, immunologic, and virologic impact of prednisolone on the chronic phase of HIV infection.     

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.     

Clinical outcome after 4 years follow-up of HIV-seropositive subjects with incomplete virologic or immunologic response to HAART

The duration of the clinical, virologic, and immunologic response to HAART, is not well defined. In this observational multi-center study 2,143 patients were enrolled classified according to virologic suppression (<500 cp/ml) and immune recovery (>100 CD4+ cells/mul from baseline) at month 12 of HAART as complete responders, virologic only responders, immunologic only responders and non-responders. Kaplan Meyer curves, multivariate and politomous regression analysis were used. Complete responders patients were 781 (36.4%), immunologic only responders 441 (20.6%), virologic only responders 336 (15.7%), and non-responders 585 (27.3%). Using multivariate analysis, being antiretroviral-naive increased the probability of having both a virologic only or a complete response and reduced the probability of an immunologic only response (P < 0.001 for all tests). Older age was associated directly with a virologic only response and inversely associated with an immunologic only response (P = 0.027 and P = 0.035, respectively). Using politomous analysis, patients baseline HIV-RNA level more than 5 log cp/ml had a 1.9-fold higher probability of an immunologic response than of a complete response (P = 0.001). After 4 years, the clinical progression rate was six times greater in non-responders, 1.9 times greater in virologic only responders, and 2.3 times greater in immunologic only responders than for responders. However, patients with virologic only response or with immunologic only response had a significantly reduced risk for clinical progression than non-responders (P < 0.001). After 4 years of HAART, the risk of clinical progression in patients with immunologic only or virologic only response is low but still higher than in complete responder patients.     

Regional changes over time in initial virologic response rates to combination antiretroviral therapy across Europe

BACKGROUND: Changes in virologic response to initial combination antiretroviral therapy (cART) over calendar time may indicate improvements in cART or emergence of primary resistance. Regional variations may identify differences in available antiretroviral drugs or patient management. METHODS: Virologic response (viral load < 500 copies/mL) 6 to 12 months after starting cART was analyzed in antiretroviral-naive EuroSIDA patients. Analyses were stratified by region (south, central west, north, east) or time started cART (early, 1996-1997; mid, 1998-1999; late, 2000-1904). RESULTS: Virologic suppression was achieved by 60% of 2102 patients: 57% south (n = 560), 61% central west (n = 466), 63% north (n = 606), 58% east (n = 470) (P = 0.091). An increase was observed over time: 52% early cART, 56% mid cART, 69% late cART (P < 0.001). Overall, there were significant effects of region (P = 0.026) and time (P < 0.001) on virologic response after adjustment for confounders. Stratified by period, regional differences were less evident (early cART, P = 0.967; mid cART, P = 0.291; late cART, P = 0.163). Stratified by region, temporal changes were observed (south, P = 0.061; central west, P < 0.001; north: P = 0.070; east, P = 0.001). CONCLUSIONS: There was some evidence of regional differences in initial virologic response to cART. Improvements over time were observed, suggesting that so far, the effect of primary resistance has not been of sufficient magnitude to prevent increasing suppression rates.     

Chinese pediatric highly active antiretroviral therapy observational cohort: a 1-year analysis of clinical, immunologic, and virologic outcomes

BACKGROUND: Few data are available on the outcomes of pediatric antiretroviral therapy (ART) in the developing world. METHODS: Eighty-three children were followed prospectively in China from July 2005 to August 2006 and received (zidovudine or stavudine) plus lamivudine plus (nevirapine or efavirenz). RESULTS: Fifty-one children were ART naive at enrollment, and 32 were ART experienced. After 12 months, median weight increased by 0.3 weight for age z-score, median CD4 count increased from 116 to 340 cells/mm (P < 0.0001), and median viral load decreased from 5.53 to <2.60 log10 copies/mL (P < 0.0001) in the previously ART-naive children. In the ART-experienced children, median CD4 count increased from 193 to 318 cells/mm (P = 0.13), despite little change in median viral load (4.85 to 4.58 log10 copies/mL; P = 0.83). The viral load was <400 copies/mL in 55% of the previously ART-naive children and in 16% of the ART-experienced children. CONCLUSIONS: Weight and CD4 cell counts improved, and more than half of previously ART-naive patients had undetectable viral loads at 1 year. Future efforts should focus on improved virologic suppression through improved adherence and access to second-line regimens.