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PubMed1998

Three year in vivo investigation to determine the progression of approximal primary carious lesions extending into dentine.

OBJECTIVE: To investigate the proportion of a sample of approximal carious lesions extending up to 1 mm into dentine which progressed over a 3-year period and to examine factors which influenced that progression. DESIGN: Prospective, single centre, clinical study. SETTING: Restorative Clinic at Bristol Dental School, UK. SUBJECTS AND METHODS: Sixty-five adult patients were identified who each had an approximal carious lesion which extended up to 1 mm into the dentine and which were assessed at intervals of up to 36 months. All patients were given appropriate preventive advice. MAIN OUTCOME MEASURES: Progression of the lesions was determined by assessment of sequential bitewing radiographs. RESULTS: 29% of the lesions progressed within 8 months, 56% by 20 months and 69% by 36 months. After 36 months, lesions which extended over 0.5 mm and up to 1 mm into the dentine were significantly more likely to have progressed (92%) compared with shallower lesions which extended up to only 0.5 mm into dentine (50%). CONCLUSIONS: The depth of an approximal dentine lesion was the main clinical marker which related to its progression. It is recommended that operative intervention is considered for approximal lesions which extend deeper than 0.5 mm into the dentine, while preventive treatment and re-assessment may be considered for shallower lesions.

Adolescent↗

PubMed2002

Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer.

Plasma levels of D-dimer are elevated in cancer patients. Activation of the extrinsic coagulation system and the fibrinolytic cascade within a tumour is thought to be related with growth, invasion and metastasis. We have investigated the relationship between these markers of fibrin metabolism, standard clinicopathological variables and serum levels of angiogenic cytokines in three cohorts: group A (n=30) consisted of 30 healthy female volunteers, group B (n=23) of consecutive patients with operable breast cancer and group C (n=84) of patients with untreated or progressive metastatic breast cancer. Plasma D-dimers, fibrinogen, IL-6, vascular endothelial growth factor and calculated vascular endothelial growth factor load in platelets are clearly increased in patients with breast cancer. D-dimers were increased in nearly 89% of patients with progressive metastatic disease. The level of D-dimers was positively correlated with tumour load (P<0.0001), number of metastatic sites (P=0.002), progression kinetics (P<0.0001) and the cytokines related to angiogenesis: serum vascular endothelial growth factor (P=0.0016, Spearman correlation=0.285), calculated vascular endothelial growth factor load in platelets (P<0.0001, Spearman correlation=0.37) and serum interleukin-6 (P<0.0001, Spearman correlation=0.59). Similarly increased D-dimer levels were positively correlated with increased fibrinogen levels (P<0.0001, Spearman correlation=0.38). The association between markers of fibrin degradation in patients with progressive breast cancer suggests that the D-dimer level is a clinically important marker for progression and points towards a relation between haemostasis and tumour progression. A role of interleukin-6, by influencing both angiogenesis and haemostasis, is suggested by these observations.

Antifibrinolytic Agents↗

PubMed2004

Diabetic retinopathy progression and visual outcome after phacoemulsification in South-Asian and Afro-Caribbean patients with diabetes.

PURPOSE: To determine diabetic retinopathy or maculopathy progression and visual outcome following phacoemulsification in South-Asian and Afro-Caribbean patients with diabetes. METHODS: Review of notes of patients with type II diabetes undergoing phacoemulsification by one surgeon. The inclusion criteria were: (a) South-Asian or Afro-Caribbean ethnicity, (b) monocular cases with a minimum postoperative follow-up of 6 months, and (c) binocular cases with an interval of at least 6 months between the operation in the two eyes. The nonoperated eye was used as control. The development or progression of diabetic retinopathy or maculopathy and final visual acuity were recorded. RESULTS: In all, 30 diabetic patients were included. There were 19 South-Asians (Pakistani, Indian, and Bangladeshi) and 11 Afro-Caribbeans. The mean (+/-SD) age was 68.9 (+/-10) years. Retinopathy or maculopathy progression was noted in seven patients (23.4%), two South-Asians, and five Afro-Caribbeans. There was no significant difference in the number of operated and fellow eyes whose retinopathy or maculopathy progressed postoperatively. Progression of retinopathy or maculopathy occurred more often in Afro-Caribbeans compared to South-Asians (P=0.02, logistic regression analysis). The mean (+/-SD) postoperative follow-up was 12.4 (+/-6.5) months. Visual acuity improved by at least two or more Snellen lines in 19 eyes (63.3%); 26 eyes (86.7%) achieved a final visual acuity of at least 6/12. CONCLUSIONS: Afro-Caribbeans may be at a higher risk of progression of retinopathy or maculopathy after phacoemulsification.

Adult↗

PubMed2005

Risk factors for progressive visual field loss in primary open angle glaucoma.

PURPOSE: The aim of this study was to evaluate routine ophthalmic data to identify clinically useful risk factors for progressive visual field loss in patients with primary open-angle glaucoma (POAG) already receiving intraocular pressure-lowering treatments. METHODS: A retrospective cohort study design was used. Routine ophthalmic data for all subjects were obtained from case records with the knowledge that baseline clinical data had been collected in a standardised manner. Progression was defined according to the AGIS visual field defect scoring system. Variables evaluated as candidate risk factors for progression were assessed by survival analysis. Factors exerting a significant effect on survival were subsequently tested in a Cox proportional hazards model. RESULTS: A cohort of 108 eligible POAG patients was followed over an average of 3.6 years, with an average visual field intertest interval of 8 months. The incidence rate of progressive loss among the cohort was 5.4 cases per 100 person years. Increasing age was found to be independently associated with a small but significantly increased risk of glaucomatous visual field defect progression (hazard ratio 1.07, P=0.022), and a borderline association was also demonstrated with being male (hazard ratio 2.76, P=0.057). CONCLUSIONS: This retrospective investigation has provided preliminary information on factors associated with increased risk of progressive glaucomatous visual field loss that may inform clinical care strategies. Lack of concordance with other studies suggests that further prospective investigations are needed if risk stratification strategies are to be employed in caring for patients with chronic open-angle glaucoma.

Age Factors↗

PubMed2006

Pointwise linear progression criteria and the detection of visual field change in a glaucoma trial.

BACKGROUND: Current pointwise linear regression (PLR) change criteria for visual field analysis are largely empirical. METHODS: Two independent sets of Humphrey Field Analyzer fields were analysed using PLR. Set i, 56 patients, and set ii, 97 patients, were followed over 16 months. Criteria were tested against set i, and then validated using set ii. Each criterion specified a fixed critical slope of 1 dB/year and with a range of significance from P<0.001 to 0.05. The criteria were varied by altering location number, cluster arrangement, and by requiring points to show change over both 12 and 16 months. True glaucomatous change was differentiated from noise by looking for exclusive progression (EP), the detection of progression without detection of improvement. RESULTS: Set i required 1 point to have a slope of 1 dB/year and P<0.05 labelled 64% progressing and 58% improving, whereas several stricter criteria were capable of detecting EP. Two points in a perimetric nerve fibre bundle (PNFB) cluster gave optimal EP detection, labelling 8.9% progressing in set i and 7.2% progressing in set ii with a cutoff P-value of 0.026 inset i and 0.013 inset ii. CONCLUSION: Lax PLR criteria detect large amounts of change. Validating criteria using two data sets allow selection of better criteria, capable of detecting EP. The criterion involving 2 points changing in a PNFB cluster offers the best option for exclusively detecting progression.

Aged↗

PubMed2000

Rising levels of serum S100 protein precede other evidence of disease progression in patients with malignant melanoma.

BACKGROUND: Several serum markers may be useful in the detection of metastatic melanoma, but none is in routine clinical use. OBJECTIVE: To assess the validity of S100 protein as a serum marker of melanoma progression. METHODS: Serum S100 protein levels were measured in 496 serum samples from 214 melanoma patients, using the Sangtec luminescence immunoassay. There were 75 patients with stage 1 melanoma, 66 initially with stage 2 melanoma, 49 initially with stage 3 melanoma and 24 with stage 4 melanoma. RESULTS: Serum S100 protein levels were < 0.2 microg L-1 in 71 of 75 (95%) stage 1 patients. One patient who had a normal level developed local recurrence. Fifty-eight of 66 (88%) stage 2 patients also had normal serum S100 protein levels. One with elevated levels progressed to stage 3 melanoma and five with elevated levels progressed to stage 4 disease. The remaining two with elevated serum S100 protein remained well. Thirty-five of 49 (71%) stage 3 patients had normal levels and, of these, two have progressed to stage 4 disease. Three patients with stage 3 disease had an elevated serum S100 protein level on one occasion but remained well. Eleven of 13 patients who developed stage 4 melanoma during the study had rising levels of serum S100 protein > 0.2 microg L-1 5-23 weeks before detection of melanoma progression by conventional means. Twenty-two of 24 patients with stage 4 disease throughout the study had consistently elevated serum S100 protein levels, and the two patients with normal levels were clinically disease free after surgery and chemotherapy. None of 14 control subjects with atypical naevi had elevated S100 protein levels, and only one of 11 healthy normal controls had an elevated level. CONCLUSIONS: Thus, rising levels of serum S100 protein are a specific and sensitive clinically relevant marker of tumour progression in melanoma patients, which precedes other evidence of melanoma recurrence.

Adult↗

PubMed2002

Inflammation is associated with progression of actinic keratoses to squamous cell carcinomas in humans.

BACKGROUND: Squamous cell carcinoma (SCC) is a common skin tumour that may metastasize and lead to death. We have observed that before actinic keratoses (AK) progress to SCCs they may become tender and inflamed. In some of these, histological examination shows that they are, in fact, SCCs. OBJECTIVES: To study the progression of AK to SCCs. METHODS: We studied skin tumours from 50 patients with either asymptomatic AK, inflamed AK or SCCs, using immunocytochemistry. The diagnosis of each tumour was confirmed by histological examination. RESULTS: Studies of differentiation using heat shock protein 27 showed a stepwise loss of differentiation as the tumours progressed from asymptomatic AK, through inflamed AK to SCCs. During the inflamed AK phase, there was a marked increase in T lymphocytes and Langerhans cells: the number of infiltrating cells diminished as progression to SCC occurred. There was an increase in immunoreactive p53 and the apoptosis inhibitor bcl-2 as tumours progressed from AK to SCCs, and a decrease in Fas and Fas ligand. CONCLUSIONS: These studies have shown that progression from benign to malignant tumours may be associated with an inflammatory response, which appears to drive malignant conversion, but subsides rapidly following this conversion.

Adult↗

PubMed1999

Histological progression during short-term follow-up of patients with chronic hepatitis C virus infection.

Assessment of prognosis from hepatitis requires liver histology. When the fibrosis stage is known, and if the fibrosis progression rate can be established, time to development of cirrhosis can be calculated. The fibrosis progression rate can be calculated from a single biopsy when duration of infection prior to biopsy is known. Sequential biopsies can also be examined. In this work, we studied histological activity and fibrosis stage in liver biopsies of 157 hepatitis C virus (HCV)-infected patients, including 92 for whom the approximate duration of infection was known. The mean fibrosis progression rate was 0.09 units per year, and was not influenced by mode of infection or viral genotype. Forty-six patients who had very mild histological changes in the initial biopsy underwent repeat biopsy 2 years later (with no intervening anti-viral treatment). Comparison of paired biopsies confirmed a tendency to histological progression and increasing hepatic fibrosis (mean, 0.15 fibrosis units per year). A normal baseline alanine aminotransferase (ALT) value was associated with slow fibrosis progression before baseline biopsy and between biopsies. These data do not differ from published cross-sectional and longitudinal studies, and suggest that histological progression will be observed during follow-up of most patients, including those with mild histological changes at time of initial assessment.

Adult↗

PubMed2003

The rate of fibrosis progression is an independent predictor of the response to antiviral therapy in chronic hepatitis C.

The response to antiviral therapy and the rate of fibrosis progression in chronic hepatitis C virus (HCV) infection are related to common factors, including age and gender. The aim of this study was to evaluate the relationship between the rate of fibrosis progression and the sustained virologic response (SVR) to interferon (IFN)-based treatment. A total of 332 patients treated for chronic HCV infection were evaluated. Using multivariate logistic regression analysis, the impact of the rate of fibrosis progression (defined as the stage of liver fibrosis according to the Metavir system/duration of infection) on the rate of SVR (negative HCV RNA at least 6 months following the end of treatment), was determined. The median age of the patients was 44 (range 25-77) years, 64% were male, and 66% were infected with genotypes 1, 4, 5 or 6. The median rate of fibrosis progression was 0.083 (range 0-2) Metavir units/year; 158 patients (48%) had F2-F4 fibrosis. After a median of 48 (range 2-126) weeks of therapy (IFN, n=190; IFN and ribavirin, n=96; pegylated IFN, n=20; pegylated IFN and ribavirin, n=26), 93 patients (28%) achieved an SVR. In univariate analysis, the rate of SVR was higher in slow [< 0.083 Metavir units/year (n=162)] than rapid progressors [> or = 0.083 Metavir units/year (n=170)] (35%vs 22%, P=0.01). After controlling for age, gender, genotype, viral load, and treatment regimen and duration, the rate of fibrosis progression remained an independent predictor of SVR (slow vs rapid progressors, OR 2.74; 95% CI 1.27-5.92; P=0.01). Hence the rate of fibrosis progression is an independent predictor of SVR to IFN-based therapy in patients with chronic hepatitis C. This additional factor should be considered in economic models evaluating this condition.

Adult↗

PubMed2003

Iris colour, ethnic origin and progression of age-related macular degeneration.

AIM: To investigate the relationship between iris colour, ethnic origin and the progression of age-related macular degeneration (AMD). METHODS: Participants were recruited from the population-based Melbourne Visual Impairment Project or the prospective, randomized, double-masked Vitamin E, Cataract and Age-Related Macular Degeneration study. From these two cohorts, 171 participants aged between 52 and 93 years who were identified as having early AMD features at their baseline examination (1992-1995) were followed for an average of 6.8 years (until 2001) to determine the progression rate of early AMD. The participants' iris colour was categorized as light, intermediate or dark. Ethnic origin was categorized as Anglo-Saxon or non-Anglo-Saxon, according to the participants' grandparents' country of birth. RESULTS: In total, 53 (31%) of the 171 participants showed signs of AMD progression. Participants with light iris colour had twofold the risk of AMD progression of those with dark or intermediate iris colours, although the age-adjusted and multivariate-adjusted associations were not significant (both P = 0.13). Age-adjusted and multivariate comparisons of Anglo-Saxon ethnic origin to non-Anglo-Saxon ethnic origin showed a noticeable but non-significant association with progression of AMD (P= 0.22 and P= 0.14, respectively). CONCLUSION: Individuals with light iris colour or of Anglo-Saxon ethnic origin had a strong tendency to greater progression of AMD. A larger sample is required to confirm these clinically important, but statistically non-significant, associations.

Aged↗

PubMed1999

Prediction of prostatic cancer progression after radical prostatectomy using artificial neural networks: a feasibility study.

OBJECTIVE: To report a methodological feasibility study in a small series of patients with node-negative organ-confined prostatic cancer, using artificial neural networks to predict tumour progression after radical prostatectomy and thus help to identify high-risk patients who would benefit from adjuvant treatment. PATIENTS AND METHODS: A group of 20 patients with pT2N0 prostatic cancer and postoperative tumour progression was compared with a control group of 20 patients with no progression, matched for age, duration of follow-up and preoperative serum prostate-specific antigen level. Histopathological data were obtained from the radical prostatectomy specimens, i.e. the Gleason score, World Health Organisation (WHO) grade and maximum diameter of the tumour transects. The volume and surface area of the epithelial tumour component and of the lumina of the neoplastic glands per unit tissue volume were estimated by morphometric methods. To predict recurrence, multilayer feedforward networks with backpropagation (MLFF-BP), two implementations of learning vector quantization (LVQ), and linear discriminant analysis (LDA) were applied. The ability of these models to correctly classify new cases was tested using the 'leave-one-out' technique. RESULTS: Progression was predicted correctly in 85% of newly presented cases from the three routine histopathological variables alone. On the basis of the four morphometric variables alone progression was predicted correctly in 93% of cases. The use of all seven variables as input data only slightly improved the quality of prediction. The best results were obtained by the LVQ networks and LDA, followed by MLFF-BP networks. CONCLUSIONS: In this methodological feasibility study, the progression of pT2N0 prostatic cancer after radical prostatectomy could be predicted with good accuracy, sensitivity and specificity from routine variables or morphometric texture variables using artificial neural networks. These results suggest that this approach should be assessed in a prospective study with more cases.

Biopsy↗

PubMed2000

Factors predictive of disease progression and death in AIDS-related Kaposi's sarcoma.

BACKGROUND: The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4+ cell counts greater than 100/microL. PATIENTS AND METHODS: We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4+ and CD8+ cell counts, plasma HIV load, p24 antigenaemia, beta2-microglobulinaemia and immunoglobin A and G serum levels. RESULTS: During a median follow-up of 22 months (3-81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9-126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression (P < 0.05). Previous and concomitant opportunistic diseases (P = 0.003) and low CD4+ cell counts (P = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival. CONCLUSION: Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4+ cell count).

AIDS-Related Opportunistic Infections↗

PubMed1998

Progression of renal failure and hypertensive nephrosclerosis.

Data provided by end-stage renal disease (ESRD) registries document a progressive and striking increase in the incidence of hypertension-related ESRD over the years, and its prevalence supports the classic statement that the kidney may be a victim of hypertension. Two clinical conditions should be considered separately when the role of hypertension in progressive renal disease is discussed: (a) hypertension and primary renal disease and (b) progressive renal disease in essential hypertension. The appearance of systemic hypertension is one of the major risk factors for the progressive deterioration of primary renal disease both in experimental models and in humans. Strict blood pressure control is able to significantly reduce the disease progression to renal failure. Angiotensin-converting enzyme inhibitors probably show a better nephroprotective action than other antihypertensive agents. Long-lasting hypertension may induce ESRD in some patients through hypertensive nephrosclerosis. In many cases of progressive renal disease associated with essential hypertension, particularly in elderly Caucasians, atheromatous renovascular disease via renal artery stenosis and/or cholesterol microembolization represent the main cause of ESRD.

Disease Progression↗

PubMed2002

Increasing expression of gastrointestinal phenotypes and p53 along with histologic progression of intraductal papillary neoplasia of the liver.

Intraductal papillary neoplasia of the liver (IPN-L) was recently proposed as the name for intraductal papillary proliferation of neoplastic biliary epithelium with a fine fibrovascular stalk resembling intraductal papillary mucinous neoplasm of the pancreas. We histochemically and immunohistochemically examined IPN-L alone or associated with hepatolithiasis, with an emphasis on the gastrointestinal metaplasia, nuclear p53 expression, and histologic progression. A total of 66 cases of IPN-L were divided into 4 groups: group 1, IPN-L with low-grade dysplasia (13 cases); group 2, IPN-L with high-grade dysplasia (20 cases); group 3, IPN-L lined with carcinoma in situ and no or microinvasion (19 cases); and group 4, group 3 with distinct invasive carcinoma (14 cases). It is suggested that IPN-L progresses from group 1 to group 4. As controls, 20 cases of nonneoplastic intrahepatic large bile ducts and 17 cases of nonpapillary invasive intrahepatic cholangiocarcinoma (ICC) were used. Biliary epithelial hypersecretion of sialomucin rather than sulfomucin was prevalent in IPN-L, and this was associated with the progression of INP-L. Immunohistochemically, cytokeratin (CK) 20 and MUC2, a gastrointestinal marker, were expressed more frequently in IPN-L than in nonneoplastic bile ducts and nonpapillary ICC (P <0.01), and their incidence were significantly increased in parallel with the progression of IPN-L (P < 0.01). In contrast, expression of CK 7, a biliary marker, was decreased in IPN-L compared with nonpapillary ICC. Nuclear p53 immunostaining was detected in 30% of IPN-L as a whole and increased in tandem with the progression of IPN-L (P < 0.01). It is suggested that IPN-L forms a spectrum of biliary epithelial neoplasia with frequent gastrointestinal metaplasia, different from the usual nonpapillary ICC, and shows stepwise progression from the perspective of mucin profile, gastrointestinal metaplasia, and p53 nuclear expression.

Adult↗

PubMed2004

The impact of competing risks on the observed rate of chronic hepatitis C progression.

BACKGROUND & AIMS: In previous studies about the natural history of chronic hepatitis C (CHC), age at the time of infection correlated with the rate at which hepatic fibrosis progresses. The presence of a competing risk, namely higher mortality from natural causes, may contribute to this observation. A simulation experiment was conducted to measure the magnitude of the effect of competing risks on the observed rate of fibrosis progression of CHC. METHODS: A computer-based probabilistic model was created in which fibrosis of CHC progressed from stage 0 to 4 (cirrhosis) in 20-year-old and 50-year-old male and female cohorts. The rate of fibrosis progression was randomly assigned to each simulated individual from a distribution common to all age- and sex-specific cohorts. The cohorts also experienced mortality from natural causes according to the 2000 census data. RESULTS: The observed median time to reach cirrhosis for the 50-year-old cohorts was 20.4 +/- 0.2 years compared with 29.7 +/- 0.2 for the 20-year-old cohorts ( P < 0.01). The median time to reach cirrhosis in men was 24.2 +/- 0.6 years compared with 25.9 +/- 0.6 in women ( P = 0.01). Overall, the observed rate of progression was slowest among young women. Similarly, accelerating mortality from natural causes, simulating the impact of comorbid conditions that shorten survival, reduced the observed time to reach cirrhosis. CONCLUSIONS: Even if the underlying rate of fibrosis progression in CHC was held constant, the time to reach cirrhosis will be observed to be substantially shorter in subjects with a higher competing mortality.

Adult↗

PubMed1999

Progression of cancer.

Carcinoma constitution originates in the hetero-duplication mitoses (4) which divide non-maturable stem cells into two different types of daughter cells: maturable and non-maturable cancerous stem cells. Throughout the progression of such mitoses, the organoid continuity of the cancer depends only on the non-maturable daughter stem cells, not on the maturable ones. This type of cancer can be considered non-progressive or to be in the incubation stage, as it only enables cancer tissue to preserve its organoid continuity without allowing progressive growth. However, when an occasional mitotic phase of the hetero-duplication mitotic progression undergoes genuine cell-phase duplication mitosis, this non-progressive or incubation stage of cancer is converted to a progressive type of cancer. This conversion is dependent on the reappearance of the complete mitotic condition of the mitotic maturation promoting system (MMPS) containing an abnormal supplement. Thus, a thorough investigation of the abnormal supplement and the reappearance of the complete mitotic condition is an essential part of research efforts to prevent and eradicate cancer.

Disease Progression↗

PubMed1996

Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS.

BACKGROUND: Clinical trials of antiretroviral drugs can take years to complete because the outcomes measured are progression to the acquired immunodeficiency syndrome (AIDS) or death. Trials could be accelerated by the use of end points such as changes in CD4+ lymphocyte counts and plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and beta 2-microglobulin, but there is uncertainty about whether these surrogate measures are valid predictors of disease progression. METHODS: We analyzed data from the Veterans Affairs Cooperative Study on AIDS, which compared immediate with deferred zidovudine therapy. Patients' plasma levels of HIV-1 RNA and beta 2-microglobulin were measured in stored plasma. RESULTS: Among the 129 patients in the immediate-treatment group, 34 had disease that progressed to AIDS, as compared with 57 of the 141 patients in the deferred-treatment group (P = 0.03). Progression to AIDS correlated strongly with base-line CD4+ lymphocyte counts (P = 0.001) and plasma levels of HIV-1 RNA (P < 0.001), but not with base-line levels of beta 2-microglobulin (P = 0.14). A decrease of at least 75 percent in the plasma level of HIV-1 RNA over the first six months of zidovudine therapy accounted for 59 percent of the benefit of treatment, defined as the absence of progression to AIDS (95 percent confidence interval, 13 to 112 percent). Plasma beta 2-microglobulin levels and CD4+ lymphocyte counts explained less of the effect of treatment. A 75 percent decrease in the plasma HIV-1 RNA level plus a 10 percent increase in the CD4+ lymphocyte count could explain 79 percent of the treatment effect (95 percent confidence interval, 27 to 145 percent). CONCLUSIONS: Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS.

BACKGROUND: From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS. METHODS: Genotyping of HLA class I loci was performed for 850 patients who seroconverted and had known dates of HIV-1 infection. Survival analyses with respect to the rate of progression to AIDS were performed to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities. RESULTS: HLA-B*35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but can bind several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY alleles by only one amino acid residue. CONCLUSIONS: This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.

Acquired Immunodeficiency Syndrome↗