Need for integration of hepatitis C (HCV) services in community-based settings for people who inject drugs: results from a global values and preferences survey.

BACKGROUND: To inform the development of updated World Health Organization (WHO) guidelines on simplified service delivery for HCV infection, a global survey was undertaken among people affected or infected by HCV. The objective of this analysis is to identify specific needs and preferences among people who inject drugs. METHODS: A multi-country, anonymous, self-administered online survey conducted in 2021 was developed by Coalition PLUS and the World Hepatitis Alliance in partnership with the WHO. Preferences for test and treat locations and simplifying HCV care were collected among people affected or infected by HCV. Chi-square tests were used to compare respondents who identified with current or former injection drug users through identification with key population to other respondents who did not identify with this key population. RESULTS: Among 202 respondents, 62 (30.7%) identified with current/former injection drug users. Compared to other respondents, they were: older [median (IQR): 48 (36-57) vs. 39 (31-51) years, p = 0.003]; more likely to have been tested for HCV (90.2% vs. 64.3%, p = 0.001); more likely to prefer testing in a community-based centre (CBC) (55.4% vs. 33.3%, p = 0.005); or in a support centres for people who use drugs (SCPUD)(50.0% vs. 9.8%, p < 0.001). The most important considerations regarding testing locations among people identified with current/former injection drug users (compared to the other respondents) were: non-judgemental atmosphere (p < 0.001), anonymity (p = 0.018) and community worker (CW) presence (p < 0.001). People identified with current/former injection drug users were more likely to prefer to receive HCV treatment in a CBC (63.0% vs. 44.8%, p = 0.028) or in a SCPUD (46.3% vs. 9.5%, p < 0.001), compared to the other respondents. The most important considerations regarding treatment locations among people identified with current/former injection drug users were the non-stigmatising/non-judgemental approach at the site (p < 0.001) and the presence of community-friendly medical personnel or CW (p = 0.016 and 0.002), compared to the other respondents. CONCLUSION: The preferences of people identified with current/former injection drug users indicated specific needs concerning HCV services. Integration of HCV services in community-based risk reduction centres may be an important element in the development of adapted services to increase uptake and retention in HCV care among this population.

Wide variation in estimates of global prevalence and burden of chronic hepatitis B and C infection cited in published literature.

To evaluate the extent of heterogeneity in global estimates of chronic hepatitis B (HBV) and C (HCV) cited in the published literature, we undertook a systematic review of the published literature. We identified articles from 2010 to 2014 that had cited global estimates for at least one of ten indicators [prevalence and numbers infected with HBV, HCV, HIV-HBV or HIV-HCV co-infection, and mortality (number of deaths annually) for HBV and HCV]. Overall, 488 articles were retrieved: 239 articles cited a HBV-related global estimate [prevalence (n = 12), number infected (n = 193) and number of annual deaths (n = 82)]; 280 articles had HCV-related global estimates [prevalence (n = 86), number infected (n = 203) and number of annual deaths (n = 31)]; 31 had estimates on both HBV and HCV; 54 had HIV-HBV co-infection estimates [prevalence (n = 42) and number co-infected (n = 12)]; and 68 had estimates for HIV-HCV co-infection [prevalence (n = 40) and number co-infected (n = 28)]. There was considerable heterogeneity in the estimates cited and also a lack of consistency in the terminology used. Although 40% of 488 articles cited WHO as the source of the estimate, many of these were from outdated or secondary sources. Our findings highlight the importance of clear and consistent communication from WHO and other global health agencies on current consensus estimates of hepatitis B and C burden and prevalence, the need for standardisation in their citation, and for regular updates.

Responses to highly active antiretroviral therapy and clinical events in patients with a low CD4 cell count: late presenters vs. late starters.

OBJECTIVE: We investigated whether adverse responses to highly active antiretroviral therapy (HAART) associated with late HIV presentation are secondary to low CD4 cell count per se or other confounding factors. METHODS: A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study of individuals starting HAART in 1998-2007 was carried out, comparing late presenters (presenting/starting HAART at a CD4 count <200 cells/µL) with late starters (presenting at a CD4 count>350 cells/µL; starting HAART at a CD4 count<200 cells/µL), using 'ideal starters' (presenting at a CD4 count>350 cells/µL; starting HAART at a CD4 count of 200-350 cells/µL) as a comparator. Virological, immunological and clinical (new AIDS event/death) outcomes at 48 and 96 weeks were analysed, with the analysis being limited to those remaining on HAART for>3 months. RESULTS: A total of 4978 of 9095 individuals starting first-line HAART with HIV RNA>500 HIV-1 RNA copies/mL were included in the analysis: 2741 late presenters, 947 late starters and 1290 ideal starters. Late presenters were more commonly female, heterosexual and Black African. Most started nonnucleoside reverse transcriptase inhibitors (NNRTIs); 48-week virological suppression was similar in late presenters and starters (and marginally lower than in ideal starters); by week 96 differences were reduced and nonsignificant. The median CD4 cell count increase in late presenters was significantly lower than that in late starters (weeks 48 and 96). During year 1, new clinical events were more frequent for late presenters [odds ratio (OR) 2.04; 95% confidence interval (CI) 1.19-3.51; P=0.01]; by year 2, event rates were similar in all groups. CONCLUSION: Amongst patients who initiate, and remain on, HAART, late presentation is associated with lower rates of virological suppression, blunted CD4 cell count increases and more clinical events compared with late starters in year 1, but similar clinical and immunological outcomes by year 2 to those of both late and ideal starters. Differences between late presenters and late starters suggest that factors other than CD4 cell count alone may be driving adverse treatment outcomes in late-presenting individuals.

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study.

OBJECTIVE: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends. METHODS: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated. FINDINGS: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load. CONCLUSIONS: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.

HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function.

The use of peptide-human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8(+) T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8(+) T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, and perforin is analyzed by FACS((R)) within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8(+) T cells compared with cytomegalovirus (CMV)-specific CD8(+) T cells in HIV chronic infection. We show that the majority of circulating CD8(+) T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-gamma and MIP-1beta but not TNF-alpha. However, a striking finding is that HIV-specific CD8(+) T cells express significantly lower levels of perforin than CMV-specific CD8(+) T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8(+) T cells are impaired in cytolytic activity.

Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations.

OBJECTIVE: Effective antiretroviral therapy (ART) has transformed the care of people with HIV, but it is important to monitor time trends in indicators of treatment success and antic future changes. METHODS: We assessed time trends from 2000 to 2007 in several indicators of treatment success in the UK Collaborative HIV Cohort (CHIC) Study, and using national HIV data from the Health Protection Agency (HPA) we developed a model to project future trends. RESULTS: The proportion of patients on ART with a viral load <50 HIV-1 RNA copies/mL increased from 62% in 2000 to 84% in 2007, and the proportion of all patients with a CD4 count <200 cells/microL decreased from 21% to 10%. During this period, the number of patients who experienced extensive triple class failure (ETCF) rose from 147 (0.9%) to 1771 (3.9%). The number who experienced such ETCF and had a current viral load >50 copies/mL rose fromz 118 (0.7%) to 857 (1.9%). Projections to 2012 suggest sustained high levels of success, with a continued increase in the number of patients who have failed multiple drugs but a relatively stable number of such patients experiencing viral loads >50 copies/mL. Numbers of deaths are projected to remain low. CONCLUSIONS: There have been continued improvements in key indicators of success in patients with HIV from 2000 to 2007. Although the number of patients who have ETCF is projected to rise in the future, the number of such patients with viral loads >50 copies/mL is not projected to increase up to 2012. New drugs may be needed in future to sustain these positive trends.

The prevalence of hepatitis C virus (HCV) infection in HIV-positive individuals in the UK - trends in HCV testing and the impact of HCV on HIV treatment outcomes.

We examined the prevalence of hepatitis C virus (HCV) infection among HIV-positive individuals in the UK, trends in HCV testing and the impact of HCV on HIV treatment outcomes. Trends over time in HCV prevalence were calculated using each patient's most recent HCV status at the end of each calendar year. Logistic regression was used to identify factors associated with having a HCV antibody test, and Cox regression was used to determine whether HCV status was associated with the time to experiencing an immunological response to highly active antiretroviral treatment (HAART), time to virological response and viral rebound. Of the 31,765 HIV-positive individuals seen for care between January 1996 and September 2007, 20,365 (64.1%) individuals were tested for HCV, and 1807 (8.9%) had detectable HCV antibody. The proportion of patients in follow-up ever tested for HCV increased over time, from 782/8505 (9.2%) in 1996 to 14,280/17,872 (79.9%) in 2007. Nine thousand six hundred and sixty-nine individuals started HAART for the first time in or after January 2000, of whom, 396 (4.1%) were HCV positive. Presence of HCV infection did not affect initial virological response, virological rebound or immunological response. The cumulative prevalence of HCV in the UK CHIC Study is 8.9%. Despite UK guidelines, over 20% of HIV-positive individuals have not had their HCV status determined by 2007. HCV infection had no impact on HIV virological outcomes or immunological response to HIV treatment. The long-term impact on morbidity and mortality remain to be determined.

WFDC1/ps20 is a novel innate immunomodulatory signature protein of human immunodeficiency virus (HIV)-permissive CD4+ CD45RO+ memory T cells that promotes infection by upregulating CD54 integrin expression and is elevated in HIV type 1 infection.

Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4(+) CD45RO(+) memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20(+) permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20(low) cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20(positive) and ps20(low/negative) isogenic clones at an early differentiation stage (CD45RO(+)/CD25(+)/CD28(+)/CD57(-)). This pattern is altered in chronic HIV infection, where ex vivo CD4(+) CD45RO(+) T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first year of highly active antiretroviral therapy.

OBJECTIVE: The aim of this study was to describe the relationship between age and the time to treatment discontinuation in the absence of virological failure as well as the development of specific laboratory abnormalities, in patients starting highly active antiretroviral therapy (HAART) for the first time. METHODS: Analyses included 8708 antiretroviral-naïve patients from the UK Collaborative HIV Cohort (CHIC) study who started HAART from 1998 onwards. We considered time to the first discontinuation of any drug in the initial HAART regimen for reasons other than virological failure; the association between this and age at the start of HAART was determined using proportional hazards regression after adjustment for potential confounders. The incidence of specific laboratory abnormalities in the first year after starting HAART was compared in those of different ages using multiple logistic regression. RESULTS: A total of 2650 patients discontinued at least one drug in their HAART regimen in the first year for reasons other than virological failure; after controlling for confounders, those aged < 30 years at the time of starting HAART were more likely to discontinue than those aged 30-39 years [relative hazard (RH) 1.12; 95% confidence interval (CI) 1.01, 1.24] as were those aged > or = 50 years (RH 1.14; 95% CI 1.00, 1.31). There were strong associations between greater age and raised total cholesterol, decreased haemoglobin and raised triglycerides over the first year, although the latter disappeared after adjustment for pre-HAART levels, suggesting that this finding reflected higher pre-HAART triglyceride levels in older individuals. CONCLUSIONS: Continued attempts to improve the tolerability of HAART regimens may help to sustain the good outcomes in all age groups over the longer term.

Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort.

BACKGROUND: It is estimated that 10%-25% of patients who start highly active antiretroviral therapy (HAART) experience immune reconstitution inflammatory syndrome (IRIS). Our objective was to determine the incidence, clinical spectrum, and predictors of IRIS in an ethnically diverse cohort of patients initiating HAART. METHODS: A retrospective study of all patients starting HAART between 1 January 2000 and 31 August 2002 at a human immunodeficiency virus (HIV) clinic in London was performed. All laboratory measurements and data on antiretroviral therapies were obtained from the clinic database. Medical records were reviewed to identify clinical events consistent with IRIS during the 6 months after HAART was initiated. RESULTS: A total of 199 patients were included, of whom 50.8% were male, 59.3% were black African, 29.1% were white, and 10.5% were black Caribbean. The median baseline CD4 cell count and HIV RNA load were 174x10(6) cells/L (interquartile range [IQR], 82-285x10(6) cells/L) and 37,830 copies/mL (IQR, 4809-149,653 copies/mL), respectively. Forty-four patients (22.7%) experienced an IRIS event at a median of 12 weeks after HAART initiation (IQR, 4-24 weeks after initiation); 22 events (50%) involved genital herpes, 10 (23%) involved genital warts, 4 (9.0%) involved molluscum contagiosum, and 4 (9.0%) involved varicella zoster virus infection. Five patients had mycobacterial infections, 4 had hepatitis B, 1 had Pneumocystis jirovecci infection, and 1 had Kaposi sarcoma. The strongest independent predictors of IRIS were younger age at initiation of HAART (P=.003), baseline CD4 cell percentage of <10% (odds ratio [OR], 2.97; IQR, 1.17-7.55) compared with >15%, and ratio of CD4 cell percentage to CD8 cell percentage of <0.15 (OR, 3.45; 95% confidence interval, 1.27-9.1) compared with >0.3. CONCLUSIONS: Approximately one-quarter of patients who start HAART experience an IRIS event. The majority are dermatological, in particular genital herpes and warts. Patients with advanced immunodeficiency at HAART initiation are at greatest risk of developing IRIS and should be appropriately screened and monitored.

Hepatitis C: global epidemiology and strategies for control.

It is estimated that globally there are approximately 100 million persons with serological evidence of current or past HCV infection, and that HCV causes about 700 000 deaths each year. The prevalence of infection is the highest in lower and middle income countries, in which a significant number of past infections were caused by iatrogenic transmission and sub-optimal injection safety. In contrast, in developed countries, infections are caused mainly by high-risk exposures and behaviours among specific populations, such as persons who inject drugs. Recently, new direct antiviral activity (DAA) oral drugs with high rates of cure over short duration, which are well tolerated, have made chronic hepatitis C a curable condition. The extraordinary clinical performance of DAAs and recent substantial price reductions and expansion in access in resource-limited settings has provided new impetus for potential control and elimination of hepatitis C as a public health threat. We review the global epidemiology of HCV and the opportunities for preventative and treatment interventions to achieve global control of HCV infection. We also summarize the key elements of the World Health Organization's first-ever global health sector strategy for addressing the viral hepatitis pandemic.

The incidence of AIDS-defining illnesses in 4883 patients with human immunodeficiency virus infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group.

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-defining illnesses are known to occur at different levels of immunosuppression, and the incidence of diagnoses may also vary according to the CD4 lymphocyte count strata. Information about the incidence of disease at different levels of immunosuppression would help clinicians monitoring patients and would allow prophylaxis to be targeted at the most appropriate population. METHODS: Between 1982 and July 1995, 4883 patients testing positive for the human immunodeficiency virus were seen at either the Royal Free or Chelsea and Westminster Hospitals in London, England. The incidence of each diagnosis, both overall and stratified by CD4 lymphocyte count, was calculated using a person-years analysis. Patients who had no CD4 lymphocyte counts measured during follow-up were excluded from the analysis. RESULTS: During a median follow-up period of 27.6 months, 3875 AIDS-defining illnesses were reported in 1713 patients. The incidence of AIDS-defining illnesses ranged from 6.22 per 100 person-years of follow-up for Pneumocystis carinii pneumonia (95% confidence interval, 5.74-6.70) to 0.37 for extrapulmonary tuberculosis (95% confidence interval, 0.26-0.48). The incidence of each AIDS-defining illness increased as the CD4 lymphocyte count declined; diagnoses such as cytomegalovirus and Mycobacterium avium-intracellulare complex infection had a low incidence at CD4 lymphocyte counts above 0.05x10(9)/L (50/mm3), while Kaposi sarcoma, P carinii pneumonia, and esophageal candidiasis had a high incidence throughout all CD4 lymphocyte count strata. CONCLUSIONS: This study provides important information about the risk of AIDS-defining illnesses at lower CD4 lymphocyte counts, enabling disease-specific prophylaxis to be targeted at the most appropriate population. In the future, as more prophylactic therapies are developed, this study will provide historical data of the incidence of diseases before specific prophylaxis was introduced.

Rate of CD4 cell decline and prediction of survival in zidovudine-treated patients.

OBJECTIVE: To investigate the relationship between survival and the rate of CD4 cell decline before and in the first year following initiation of zidovudine (ZDV) therapy. DESIGN: Retrospective observational study. SETTING: Hospital-based HIV clinics within the Riverside District Health Authority in London. PATIENTS: Patients (total, 1415) with AIDS (n = 476), symptomatic (n = 687) or asymptomatic (n = 194) HIV-1 infection, or of unknown clinical status (n = 58), who first received ZDV between June 1986 and October 1991. INTERVENTION: The majority of patients received ZDV at an initial dose of 200 mg every 6 h or 250 mg twice daily. The median duration of follow-up after receipt of ZDV was 17 months (range, 2-54 months). MAIN MEASUREMENTS: CD4 cell counts prior to and following initiation of ZDV; rate of decline of log-transformed CD4 cell count before ZDV therapy and during the first year of therapy; survival. RESULTS: As of 31 December 1991, 432 patients had died. Patients with the highest rate of log CD4 decline before initiation of ZDV (< or = -0.06 log cells per month) as well as in the first year of ZDV therapy (< or = -0.08 log cells per month) had a much poorer 3-year survival from initiation of ZDV (23 and 40.5%, respectively) compared with patients with no decline or an increase in their CD4 count before (39.0%) or after (72.3%) ZDV therapy. In a series of multivariate analyses, a high rate of log CD4 decline in the first year of ZDV therapy (< or = -0.08 log cells per month) was predictive of poor survival, after adjustment for age and clinical status at initiation of ZDV and most recent CD4 count. In contrast, rate of CD4 decline before ZDV, presence of an initial CD4 rise and the magnitude of change in the rate of CD4 decline following ZDV were no longer significantly associated with outcome. CONCLUSIONS: In this retrospective study, the rate of CD4 decline in the first year of ZDV therapy, but not the occurrence of an initial CD4 rise was predictive of survival, suggesting that the early CD4 response may be a poor measure of the impact of ZDV. Patients with a high rate of CD4 decline despite ZDV therapy represent a subgroup of patients with a poor prognosis who might benefit from alternative or combination antiretroviral therapies.

Long-term survival in patients with advanced immunodeficiency.

OBJECTIVE: To identity prognostic factors associated with survival time in HIV-infected patients with advanced immunodeficiency. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1284 HIV-infected patients with serial CD4 count measurements and at least one CD4 cell count < or = 50 x 10(6)/I (CD4 < or = 50). MAIN OUTCOME MEASURE: Survival from initial CD4 cell count < or = 50 x 10(6)/l. RESULTS: The median survival from initial CD4 < or = 50 x 10(6)/l was 17.1 months. The risk of death increased by 2% 195% confidence interval (Cl), 1-31 for each year of age, by 10% (95% Cl, 3-16) for each 10 x 10(6)/l decrease in CD4 count, and by 14% (95% Cl, 9-18) for each 1 g/dl decrease in haemoglobin level. Compared to AIDS-free patients with CD4 < or = 50 x 10(6) cells/l, the risk of dying was 1.5-fold (95% Cl, 1.2-1.9) that of patients who had an AIDS diagnosis for fewer than 3 months prior to CD4 < or = 50, 1.8-fold for patients with an AIDS diagnosis for 4-11 months prior to CD4 < or = 50, and twice that of patients with AIDS for > or = 12 months prior to CD4 < or = 50. The risk of dying for patients whose rate of CD4 cell decline was > 40 x 10(6)/l per 6 months was 1.7-fold (95% Cl, 1.3-2.3) that of patients with an average CD4 cell loss < 40 x 10(6)/l per 6 months, after adjusting for age, haemoglobin and duration of AIDS prior to CD4 < or = 50 x 10(6) cells/l. A prognostic score was developed from the final multivariate model, based on age at CD4 < or = 50, haemoglobin at CD4 < or = 50, duration of AIDS and rate of CD4 decline prior to CD4 < or = 50. CONCLUSIONS: Routinely available clinical and laboratory data including haemoglobin level, rate of CD4 decline and duration of AIDS can be readily translated into a prognostic score and then used to predict the survival experience of an HIV-infected patient with advanced immunodeficiency.

Ten-year trends in CD4 cell counts at HIV and AIDS diagnosis in a London HIV clinic.

OBJECTIVE: To examine temporal trends (1986-1996) in the CD4 cell count at first HIV-1 positive test and initial AIDS diagnosis, and the influence of selected patient characteristics and treatment factors on these trends. DESIGN: A retrospective clinic-based study. SETTING: Three hospital-based clinics in West London. PATIENTS: A group of 5921 adult HIV-1-seropositive persons and 2835 reported patients with AIDS over a 10-year period from 1 January 1986 to 1 October 1996. METHODS: The CD4 cell count at HIV diagnosis (CD4HIV) was defined as the nearest CD4 cell count to within 2 months of HIV diagnosis; and the CD4 cell count at AIDS diagnosis (CD4AIDS) as the last CD4 cell count in the two months prior to the development of AIDS. Simple and multiple linear regression analysis were used to examine the influence of selected covariates on CD4HIV and CD4AIDS. RESULTS: The percentage of patients with an available CD4HIV and CD4AIDS increased from less than 5% in 1987 to 53% and 40%, respectively, in 1990, and 79% and 48%, respectively, in 1996. Patients with a missing CD4HIV or CD4AIDS were younger and less likely to have received antiretroviral therapy or prophylaxis for Pneumocystis carinii pneumonia (PCP). There was no significant change in CD4HIV over a 10-year period (median 334 x 10(6) cells/l), but a lower CD4HIV was associated with older age at presentation and injecting drug use. There was a delay in the onset of clinical AIDS, with a fall in the median CD4AIDS value from 99 x 10(6) cells/l prior to 1987, to 58 x 10(6) cells/l in 1990, 68 x 10(6) cells/l in 1994 and 60 x 10(6) cells/l in 1996; this decline in onset was seen for PCP as well as for cytomegalovirus and atypical mycobacterial infections. At all time periods, a lower CD4AIDS was associated with combined use of antiretroviral therapy and PCP prophylaxis. After adjustment for use of antiretroviral therapy and PCP prophylaxis prior to AIDS diagnosis, year of diagnosis was no longer associated with CD4AIDS. There was a significant trend towards an improved survival following AIDS diagnosis from 20.1 months prior to 1988, to 20.3 months (1989-1990), 21.0 months (1991-1992) and 22.1 (1993-1994) (P < 0.0005). CONCLUSIONS: The observed decline in CD4AIDS value was related to the introduction of antiretroviral therapy in 1988, and PCP prophylaxis in 1989. Temporal changes in the CD4 cell count at HIV and AIDS diagnosis among different demographic groups can provide insights into the changing natural history of the HIV epidemic and access to medical care. We recommend monitoring of the CD4 cell count at new HIV and AIDS diagnosis and at initiation of antiretroviral therapy as additional measures in national HIV/AIDS surveillance.

Racial differences in rate of CD4 decline in HIV-1-infected homosexual men.

OBJECTIVE: To determine whether racial differences exist in the rate of CD4 lymphocyte decline in HIV-1-infected homosexual men. DESIGN: Prospective cohort study. STUDY POPULATION: Non-Hispanic white (n = 321) and black (n = 102) HIV-1-seropositive homosexual and bisexual men were recruited from the Baltimore/Washington, DC metropolitan areas between 1984-1985 and 1987-1990, and evaluated semiannually. MAIN MEASUREMENTS: Changes in CD4 lymphocyte count and CD4 percentage over time were analysed using linear regression methods for the 271 white and 69 black participants who had at least four semiannual CD4 lymphocyte measurements. RESULTS: Rate of decline in CD4 lymphocyte count over 6 months was much slower among black than white seroprevalent men at all levels of baseline CD4 count (baseline 201-400 x 10(6)/l: + 0.24 versus -17.7 x 10(6)/l; 401-600 x 10(6)/l: -11.3 versus -23.9 x 10(6)/l; 601-800 x 10(6)/l: -15.1 versus -35.2 x 10(6)/l; > 800 x 10(6)/l: -4.3 versus -42.7 x 10(6)/l for black versus white, respectively), although this was only statistically significant for the lowest and highest strata of baseline CD4 count. These racial differences persisted after adjustment for recruitment period (1984-1985 or 1987-1990), follow-up duration, age and zidovudine therapy or Pneumocystis carinii pneumonia prophylaxis. Similar findings were observed among the 70 white and 11 black seroconverters. Black participants were also less likely than a subgroup of white participants matched on baseline CD4 lymphocyte count to be HIV-1 p24 antigen-positive. However, after acid dissociation of samples initially p24 antigen-negative, there were no significant differences in the prevalence of p24 antigenemia at enrollment or after 1 year of follow-up. CONCLUSIONS: This analysis suggests a more gradual decline in CD4 lymphocyte count among black than white Americans. The clinical significance of and reasons for this are unclear, but the lower prevalence of p24 antigenemia due to immune complexing among black Americans suggests that racial differences in the immune response to HIV may exist. Additional studies are needed to validate these findings in a larger cohort of non-whites, and to assess their relationship with other measures of cell-mediated immune function.

Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. National Prospective Monitoring System Steering Group.

OBJECTIVE: To investigate the relationship between changing morbidity patterns, the use of hospital services by HIV-infected patients and the uptake of antiretroviral therapy (ART) in England. DESIGN: Prospective serial cross-sectional analyses based on data collected through the National Prospective Monitoring System (NPMS), a multi-centre prospective monitoring system. SETTING: HIV-infected patients seen in 10 clinics, five London and five non-London, during the three semesters, 1 January 1996 to 30 June 1997. MAIN OUTCOME MEASURES: The mean use of hospital services per patient-year, mean new HIV-related opportunistic illnesses per 1000 patient-years and percentage uptake of ART. RESULTS: The use of inpatient services changed particularly among AIDS patients. The mean number of inpatient days for AIDS patients decreased from 19.7 [95% confidence interval (CI) 13.7-25.7] in 1996 to 11.2 (95% CI 6.1-15.6) per patient-year in 1997. Concurrently the number of new AIDS-defining events decreased significantly from 567 (95% CI 529-607) to 203 (95% CI 183-225) per 1000 patient-years. The overall uptake of ART increased significantly from 33% (95% CI 31-35%) to 50% (95% CI 48-52%), and a switch from mono or dual to triple therapy or quadruple or more therapy was observed. However, by mid-1997 only 29% (95% CI 26-32%) of asymptomatic patients and 51% (95% CI 49-54%) of patients with symptomatic non-AIDS were on ART, compared with 69% (95% CI 66-71%) of AIDS patients. CONCLUSION: The observed reduction in new AIDS-defining events has led to a reduction in the need for inpatient hospital care and has been associated with an increased uptake of ART, including a switch to triple therapy. All of these factors are likely to have contributed to the observed reduction in mortality among English AIDS patients. As the overall uptake of ART remained relatively low in English centres further improvements can be anticipated. However, the medium to long-term effects of these treatment regimens will need to be closely monitored.

Progressive CD4 cell depletion and death in zidovudine-treated patients.

Preliminary evidence suggests that a CD4 cell count < 50 cells/mm3 is associated with a particularly poor short-term prognosis, and is both necessary and sufficient for death associated with HIV infection. We sought to validate these findings in a cohort of 1,415 zidovudine (ZDV)-treated patients, with advanced HIV infection, and to examine more closely the profile of CD4 cell decline over the 2 years prior to death. As of December 31, 1991, 432 patients had died. The cumulative 2 year survival of patients once their CD4 cell count fell to < or = 50 cells/mm3 (median survival = 17.3 months) was substantially shorter at 25.7%, than from when their CD4 cell counts first fell within the range 51-100/mm3 (51.4%); 101-150/mm3 (67.3%); or 151-200/mm3 (76.5%). The percent of patients with a CD4 count < 50 cells/mm3, increased from 33% at 24 months prior to death to 58% at 12 months and 86% at 1 month. Patients with a CD4 count > or = 50 cells/mm3 in the month prior to death, were significantly older (p < 0.001) and had higher CD4 cell counts (p < 0.05) at initiation of ZDV compared to those with a CD4 count < 50 cells/mm3. There were no important differences in HIV risk category, duration of ZDV therapy or use of PCP prophylaxis between the two groups. These findings highlight the importance of more intensive monitoring of patients with CD4 counts < 50 cells/mm3, since life-threatening opportunistic infections are more likely to supervene at this stage. A CD4 count < 50 may also be a useful surrogate endpoint for survival in clinical trials.

Association between a defective CCR-5 gene and progression to disease in HIV infection.

We measured the effect(s) of CCR-5 genotype on disease progression by studying the frequency of a defective CCR-5 delta32 allele within a cohort of long-term infected individuals. An elevated frequency of CCR-5 delta32 heterozygotes within the cohort compared with a control population of blood donors was observed. An association between progression rate and CCR-5 delta32 heterozygosity was observed. Furthermore, analysis of proviral DNA V3 sequences from a subset of the cohort predicted that the majority of individuals (39 of 44) were infected with viruses predicted to utilize the beta-chemokine receptor CCR-5. The marked association between CCR-5 genotype and disease progression observed in this study may be a consequence of the predicted low frequency of CXCR-4-utilizing viruses present within the selected cohort.

Relationship between CD4 count and CD4% in HIV-infected people.

OBJECTIVE: To describe the relationship between absolute CD4 count and CD4%, and the influence on this of gender, risk group, age, a diagnosis of AIDS, use of zidovudine (ZDV) therapy and PCP prophylaxis. METHODS: 9203 paired serial measurements of CD4 count and CD4% on 1017 initially AIDS-free and ZDV-naive HIV positive patients from a London-based cohort were available for analysis. Multi-level regression procedures were used on log-transformed data to relate values of CD4 count to a given level of CD4%. We estimated the effect of selected covariates on this relationship from the exponent of the covariate coefficient. RESULTS: A strong linear relationship was found between log CD4 and log CD4%, CD4 = e 1.78(CD4%)1.26 or 5.93 (CD4%)1.26 (excluding covariates). Based on this model, a CD4% of 5%, 15%, and 30% corresponded to an estimated CD4 count (95% confidence interval [CI]) of 45 cells/mm3 (17-117 cells/mm3), 182 cells/mm3 (64-499 cells/mm3) and 438 cells/mm3 (132-1395 cells/mm3), respectively. However, after adjustment for selected covariates, the predicted CD4 count for a given CD4% was found to be lower among heterosexuals and injecting drug users as compared with homosexual men by 30% and 17% respectively; following an AIDS diagnosis by 21%; and after initiation of ZDV therapy and PCP prophylaxis by 19% and 10%, respectively. CONCLUSION: This analysis should be useful to clinicians and researchers in relating values of CD4 count to CD4%, although we have demonstrated that this is not a simple relationship. The wide CI observed in the estimated CD4 count particularly at high CD4% values, and the adjustments necessary according to risk group, following an AIDS diagnosis and use of ZDV and PCP therapy limit its application in the clinical setting.