Late HAART Era Research Articles

The burden of non-communicable diseases and mortality in people living with HIV (PLHIV) in the pre-, early- and late-HAART era.

ObjectivesTo estimate the burden of non‐communicable diseases (NCDs) and mortality among PLHIV in the pre‐, early‐ and late‐HAART (highly active antiretroviral therapy) era.MethodsWe conducted a cohort study using population‐based Danish medical registries including all adult HIV‐infected residents of the Central Denmark Region during 1985–2017. For each HIV patient, we selected 10 comparisons from the background population matched by age, sex and municipality of residence. Based on hospital‐related diagnoses we estimated the prevalence and incidence of specific NCD at diagnosis and at 5 and 10 years.ResultsWe identified 1043 PLHIV and 10 430 matched comparisons. PLHIV had lower socioeconomic status and more were born outside western Europe. At HIV diagnosis, 21.9% of PHLIV vs. 18.2% of non‐HIV individuals had at least one NCD, increasing to 42.2% vs. 25.9% after 10 years. PLHIV had higher prevalence and cumulative incidence of alcohol abuse, chronic obstructive pulmonary disease (COPD), ischaemic heart disease, mental disorders, renal and liver disease, but no increased risk of diabetes mellitus. Only PLHIV in the age groups 41–50 and > 51 years had an increased incidence of osteoporosis. From the pre‐ to the late‐HAART era, 10‐year mortality among PLHIV decreased from 45.5% to 9.4% but continued at more than twice that of uninfected comparisons. However, in the late‐HAART era, the mortality of PLHIV who were alive 2 years after HIV diagnosis was approaching that of comparisons.ConclusionsEven in the late‐HAART era, PLHIV have an excess mortality, which may be attributable to several NCDs being more prevalent among PLHIV. The prevalence rates of ischaemic heart disease, diabetes, osteoporosis and renal disease tend to increase over calendar time. Therefore, improvement of survival and quality of life of PLHIV neets strategies to reduce the risk of developing NCDs, including avoiding toxic antiretroviral therapy and lifestyle changes.

High prevalence and incidence of HPV-related anal cancer precursor lesions in HIV-positive women in the late HAART era

IntroductionAnal cancer is one of the most common non-AIDS defining malignancies, especially in men who have sex with men and women living with HIV (WLHIV). ObjectivesTo evaluate the prevalence and incidence of precursor lesions (high-grade squamous intraepithelial lesions [HSIL]) and anal cancer in our cohort of women and to compare them to cervical lesions; to calculate the percentage of patients that acquire and clear oncogenic genotypes (HR-HPV) in the anal canal; and to determine predictive factors for anal HPV infection. Patients and methodsProspective-longitudinal study (May 2012–December 2016). At baseline (V1) and follow up visits, anal mucosa samples were taken in liquid medium for cytology and HPV PCR. In cases of abnormal anal cytology and/or positive HR-HPV PCR results, a high resolution anoscopy was performed. Patients were also referred to the gynaecologist. ResultsNinety five women with an average age of 43.7 years were included. At baseline, 11.6% had cervical abnormalities (4.1% CIN1, 2.2% CIN2/3, 1.1% cervical cancer), 64.3% anal abnormalities (50% LSIL/AIN1, 9.5% HSIL/AIN2/3 and 2.4% anal cancer) and 49.4% had HR-HPV genotypes. During 36 months of follow up, the incidence of anal HSIL was 16×1000 person-years; 14.8% acquired HR-HPV genotypes and 51.2% cleared them, p=0.007. No patients presented CIN1/2/3/ or cervical cancer. In the multivariate analysis we found the following predictive factors for HR-HPV infection: smoking (RR: 1.55, 95% CI: 0.99–2.42), number of sexual partners >3 (RR: 1.69; 95% CI: 1.09–2.62), cervical and anal dysplasia (RR: 1.83; 95% CI: 1.26–2.67) and (RR: 1.55; 95% CI: 1.021–2.35), respectively. ConclusionsDespite clearance rates of anal oncogenic genotypes being higher than acquisition rates, prevalence and incidence of HSIL were still high and greater than cervical HSIL. Therefore, screening for these lesions should perhaps be offered to all WLHIV.

Non-AIDS-Defining Cancer Mortality: Emerging Patterns in the Late HAART Era.

Non-AIDS-defining cancers (non-ADCs) have become the leading non-AIDS-related cause of death among people with HIV/AIDS. We aimed to quantify the excess risk of cancer-related deaths among Italian people with AIDS (PWA), as compared with people without AIDS (non-PWA). A nationwide, population-based, retrospective cohort study was carried out among 5285 Italian PWA, aged 15-74 years, diagnosed between 2006 and 2011. Date of death and multiple-cause-of-death data were retrieved up to December 2011. Excess mortality, as compared with non-PWA, was estimated using sex- and age-standardized mortality ratios (SMRs) and the corresponding 95% confidence intervals (CIs). Among 1229 deceased PWA, 10.3% reported non-ADCs in the death certificate, including lung (3.1%), and liver (1.4%), cancers. A 7.3-fold (95% CI: 6.1 to 8.7) excess mortality was observed for all non-ADCs combined. Statistically significant SMRs emerged for specific non-ADCs, ie, anus (5 deaths, SMR = 227.6, 95% CI: 73.9 to 531.0), Hodgkin lymphoma (12 deaths, SMR = 122.0, 95% CI: 63.0 to 213.0), unspecified uterus (4 deaths, SMR = 52.5, 95% CI: 14.3 to 134.5), liver (17 deaths, SMR = 13.2, 95% CI: 7.7 to 21.1), skin melanoma (4 deaths, SMR = 10.9, 95% CI: 3.0 to 27.8), lung (38 deaths, SMR = 8.0, 95% CI: 5.7 to 11.0), head and neck (9 deaths, SMR = 7.8, 95% CI: 3.6 to 14.9), leukemia (5 deaths, SMR = 7.6, 95% CI: 2.4 to 17.7), and colon-rectum (10 deaths, SMR = 5.4, 95% CI: 2.6 to 10.0). SMRs for non-ADCs were particularly elevated among PWA infected through injecting drug use. This population-based study documented extremely elevated risks of death for non-ADCs among PWA. These findings stress the need of preventive interventions for both virus-related and non-virus-related cancers among HIV-infected individuals.

Impact of Age-related Comorbidities on Five-year Overall Mortality among Elderly HIV-Infected Patients in the Late HAART Era--Role of Chronic Renal Disease.

To identify main prognostic factors for 5-year mortality among age-related comorbidities (ARCs) in older people living with HIV (PLHIV). A prospective, multicentre cohort study with a 5-year follow-up period in the late HAART era (from January 2008 to December 2012). The Dat'AIDS cohort involving 12 French hospitals. All actively followed HIV-1 infected patients aged 60 or older. The study endpoint was all-cause five-year mortality. The following ARCs were considered: chronic renal disease, cardiovascular diseases, cancer, chronic pulmonary disease, cirrhosis, diabetes and nutritional status. Hepatitis C (HCV), hepatitis B (HBV) co-infection and sociodemographic characteristics were also evaluated. Cox's Proportional Hazards model was used for multivariate analysis. Among 1415 PLHIV aged 60 or more patients included, mean age was 66±5.5 years; 154 died (mortality rate 2.47/100 patient-years). The most prevalent ARCs were chronic renal disease (20.1%), diabetes (14.2%) and cardiovascular diseases (12.2%). By multivariate analysis, chronic renal disease (adjusted hazard ratio (aHR)=2.25; 95% confidence interval (CI) [1.58-2.21]; p<10-4), cardiovascular diseases (aHR=2.40; 95%CI[1.64-3.52]; p<10-4), non-HIV related cancer (aHR=1.91; 95%CI[1.20-3.05]; p=0.007), cirrhosis (aHR=2.99; 95%CI[1.68-5.33]; p<10-3), HCV co-infection (aHR=2.00; 95%CI[1.18-3.38]; p=0.009), low body mass index (aHR=2.42; 95%CI[1.46-4.01]; p<10-3) and CD4 cell count < 200 cells/µl (aHR=2.23; 95%CI[1.36-3.65]; p=0.002) were independently associated with 5 year mortality. Due to a high prevalence, chronic renal disease and cardiovascular disease are main prognostic factors for 5-year mortality among aged PLHIV.

Influence of residential segregation on survival after AIDS diagnosis among non-Hispanic blacks

PurposeNon-Hispanic blacks (NHBs) are disproportionately affected by the AIDS epidemic. With the advent of highly active antiretroviral therapy (HAART), survival after AIDS diagnosis has increased dramatically, yet survival among NHBs is shorter compared with non-Hispanic whites. Racial residential segregation may be an important factor influencing observed racial disparities in survival. MethodsWe linked data on 30,813 NHBs from the Florida Department of Health HIV/AIDS Reporting system (1993–2004) with death records and applied segregation indices and poverty levels to the data. Weighted Cox models were used to examine the association between segregation measured on five dimensions and survival, controlling for demographic factors, clinical factors, and area-level poverty. Analyses were stratified by pre-HAART (1993–1995), early HAART (1996–1998), and late-HAART (1999–2004) eras. ResultsIn the late-HAART era, adjusting for area-level poverty, segregation remained a significant predictor of survival on two dimensions: Concentration (hazard ratio, 1.32; 95% confidence interval, 1.13–1.56) and centralization (hazard ratio, 1.44; 95% confidence interval, 1.12–1.84). Area-level poverty was an independent predictor of survival. ConclusionsThese findings suggest that certain dimensions of segregation and poverty are associated with survival after AIDS diagnosis.

Pneumocystis jirovecii pneumonia in HIV-1-infected patients in the late-HAART era in developed countries

In developed countries with free access to health care, primary chemoprophylaxis with co-trimoxazole, and antiretroviral treatment, Pneumocystis pneumonia (PCP) in HIV-infected subjects should be restricted to undiagnosed late presenters. We retrospectively identified confirmed PCP hospital admissions in HIV-1 patients (period 1986-2010) and examined their characteristics and factors associated with mortality. Three hundred and twelve episodes (median CD4 27 cells/μl) were identified during 3 periods: pre-HAART (1986-1995), 49%; early-HAART (1996-1999), 17.3%; and late-HAART (2000-2010), 33.7%. PCP was the initial AIDS-defining diagnosis in only 86 (27.6%). Thirty-four (10.9%) patients died during their hospital stay, without a significant reduction in mortality in recent periods (p = 0.311). However, the 12-month mortality decreased through the periods (33.3% to 16.2%; p = 0.003). Drug users (p = 0.001) and those naïve to HAART (p < 0.001) decreased in the late-HAART era, while heterosexuals (p = 0.001), immigrants (p < 0.001), and HAART initiation before hospital discharge (p < 0.001) increased. A partial pressure of oxygen (PaO2) ≤ 55 (p = 0.04), intensive care admission (p < 0.001), and the absence of HAART initiation before discharge (p = 0.02) were correlated with mortality. The epidemiology and 12-month mortality of HIV-1-infected subjects with PCP have changed significantly in the late-HAART era, while mortality during hospital stay has remained unchanged. HIV diagnosed individuals lost to follow-up in care have emerged as the main driver of PCP in developed countries. Like HIV late presenters, they are more likely to have AIDS-defining illnesses, to be hospitalized, and to die. This finding has important implications for the design of better strategies to retain HIV-1-infected individuals in care.

Declining incidence of AIDS-defining opportunistic illnesses

To measure the incidence and risk factors of AIDS-defining opportunistic illnesses (AOIs) in the pre-highly active antiretroviral therapy (HAART) (1993-1995), early-HAART (1996-2000), and late-HAART (2001-2008) periods. Prospective cohort analysis of AIDS surveillance data. Individuals living with, or diagnosed with AIDS from 1993 through 2008 were included. Poisson regression models were used to estimate annual incidence rates of the eight most frequently occurring AOIs, and to compare these rates in the pre-HAART (1993-1995), early-HAART (1996-2000), and late-HAART (2001-2008) periods. There were 18 733 individuals with AIDS included; 5788 were diagnosed prior to 1993 and 12 945 were diagnosed between 1 January 1993 and 31 December 2008. The incidence rates of Pneumocystis jiroveci pneumonia, wasting syndrome, Kaposi's sarcoma, HIV encephalopathy, cytomegalovirus retinitis, cytomegalovirus, and esophageal candidiasis decreased during the study period, with the largest declines observed between the pre-HAART and early-HAART periods. Incidence rates also decreased between the early-HAART and late-HAART periods, though not as sharply. Incidence rate reductions between the earliest and latest period ranged from 84 to 99%. Steep declines in incidence of AOIs were found following the introduction of HAART and continued into the late-HAART era. These declines reflect the impact of HIV diagnosis and treatment on a population level.

Beyond Virological Suppression: The Role of Adherence in the Late Haart Era

HAART has increased the life expectancy of HIV-infected individuals significantly. Optimal adherence to HAART results in viral suppression and immune recovery in the majority of HIV-infected persons. Data from the early HAART era suggest that adherence levels of greater than 95% are necessary to achieve and maintain virological suppression. However, the optimal threshold of adherence required to maximize the pharmacological benefits of contemporary antiretroviral regimens, particularly in the virologically suppressed patient, is unknown. This review examines new data on the role of adherence in the late HAART era, focusing on virological, immunological and epidemiological aspects. We begin with a discussion of the impact of adherence on viral dynamics and immunological parameters in the virologically suppressed patient. We then review the importance of adherence in emerging antiretroviral treatment strategies. Finally, we summarize accumulating data on the role of antiretroviral adherence in the prevention of HIV transmission. Taken together, the data reviewed reinforce the critical importance of adherence in the management of HIV infection in the late HAART era.

Demographics and survival of AIDS cases with cancer, Washington, DC, 1996-2006

Background Washington, DC (DC) has one of the highest HIV/AIDS rates in the U.S and cancer is the second leading cause of death among DC residents. This study sought to examine the demographic characteristics and survival of persons with AIDS defining cancers (ADCs) compared to those with non-AIDS defining cancers (NADCs) between the early HAART era (1996-2001) and the late HAART era (2002-2006) in DC.

Incidence, Temporal Trends, and Predictors of Thrombocytopenia Among HIV-Infected Persons Treated with Combined Antiretroviral Therapy (cART)

AbstractAbstract 69 Background:Thrombocytopenia (TP) is a relatively common disorder in HIV-infected Persons, and may be a challenging illness to treat, mainly because of its multifactorial aetiology. The underlying pathophysiology includes accelerated immune-mediated peripheral PLT destruction and impaired PLT production by the infected megakaryocytes of the bone marrow. Moreover, TP can also occur as a secondary phenomenon in HIV-positive patients, due to hypersplenism, bone marrow infiltration from infections of lymphoma, or myelosuppressive effects of medications. However, the epidemiology and predictors of TP in the era of potent HIV antiretroviral therapy has not been well defined. In a recent retrospective-matched case–control study of HIV-infected adult outpatients with (n=73) and without (n=73) TP, authors found that TP was significantly associated with HCV infection, cirrhosis, and uncontrolled HIV replication (Marks KM et al. J AIDS 2009). Antiretroviral therapy interruption among patients with well-controlled HIV infection has been associated with an increased incidence of thrombocytopenia, especially among those with a low baseline platelet count or a history of HIV-related thrombocytopenia (Bouldouyre MA et al. J AIDS 2009). Methods:The study was carried out in the Icona Foundation Study Cohort. All previously naïve starting cART with normal value of platelet count (PC) were included. TP has been defined as PC <100 × 109/L persisting in at least 2 consecutive determinations for at least 3 consecutive months. For each patient person-years of follow-up (PYFU) while receiving cART were calculated, and used to estimate the incidence rate of TP. A multivariable Poisson model was performed to elucidate the contribution of HIV viremia, immune reconstitution, HCV infection, ARV drug-class, and other potential risk factors for TP. Current HIV-RNA and CD4 count entered into the model as time-dependent covariates. Results:A total of 2,771 patients were included: 69.4% male, median age 36 yrs (IQR: 32–41), 38.5% HCV+. At initiation of cART, CD4 count and HIV-RNA were 295 cells/mmc and 4.75 log10 cp/mL, respectively. Mean value of baseline PC was 189 × 109/L (IQR 149–231). Overall patients contributed to 13,787 PYFU. During follow-up, 105 patients developed a TP accounting for an incidence rate of 7.6/1000 PYFU (95%CI 6.3–9.2). PC <20,000 was found in 5.7%, 20,000-50,000 in 12.4%, 50,000-100,000 in 81.4%. A trend for a reduction in the TP incidence rates over the last years was found (1997-1999: 9.8/1000 pyrs; 2000–2004: 4.6/1000 pyrs; 2005–2009: 4.5/1000 pyrs; P at Chi-square for temporal trend<0.001). At multivariable model, a higher risk of TP was associated with male gender (HR 1.99; 95%CI 1.19–3.32; P=0.008), and HCV co-infection (HR 3.45; 95%CI 2.23–5.33; P<0.001). Moreover, both lower level of current CD4 (HR 1.67 for 0–200 vs >350 cell/mmc; 95%CI 1.02–2.64; P=0.039) and detectable HIV viremia (HR 1.47 for each log10 cp/ml increase; 95%CI 1.25–1.73; P<0.001) were significantly associated with TP onset. No association with ARV drug-class was found. Conclusions:Thrombocytopenia remains a relatively common disorder in the late HAART era, with an overall 7.6 * 1000 PYFU, even if a trend for a reduced incidence over the last years was observed. In a large unselected cohort of antiretroviral naïve starting treatment, HCV co-infection, cirrhosis at baseline, uncontrolled HIV replication and lower current CD4 count were all independent predictors of TP. Furthermore in our study, the association with HCV-infection was independent from cirrhosis suggesting that mechanisms other than advanced liver disease may play a role in HIV/HCV-coinfected patients. In this cohort of treated patients, we found a strong association of TP with uncontrolled HIV replication and lower current CD4, these findings confirm the benefit of antiretroviral therapy on HIV-related thrombocytopenia.ON BEHALF OF THE ICONA FOUNDATION STUDY GROUP Disclosures:No relevant conflicts of interest to declare.

Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study.

To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development. Retrospective analysis of a multicenter, prospective natural history study including 4498 HIV-infected US military beneficiaries with 33 486 person-years of follow-up. Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre (1984-1990), late pre (1991-1995), early post (1996-2000), and late post (2001-2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer. Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person-years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (P < 0.001). Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7, P = 0.0004). During the late HAART era, 71% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, noncancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age and white race (due to skin cancers). Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART use is protective for ADCs, but did not significantly impact NADCs.

Comparisons of Causes of Death and Mortality Rates Among HIV-Infected Persons

Comparisons of death-related variables during the 3 eras were performed. The number of deaths declined over the study period, with 987 deaths in the pre-HAART era, 159 deaths in the early HAART era (1997-1999), and 78 deaths in the late HAART era (2000-2003) (P < 0.01). The annual death rate peaked in 1995 (10.3 per 100 patients) and then declined to <2 deaths per 100 persons in the late HAART era (P < 0.01). The proportion of deaths attributable to infection decreased, but infection remained the leading cause of death in our cohort, followed by cancer. Of those who died, there was an increasing proportion of non-HIV-related deaths (32% vs. 9%; P < 0.01), including cardiac disease (22% vs. 8%; P < 0.01) and trauma (8% vs. 2%; P = 0.01) in the post-HAART versus pre-HAART era. Despite the absence of intravenous drug use and the low prevalence of hepatitis C coinfection in our cohort, an increasing proportion of deaths in the HAART era were attributable to liver disease, although the numbers are small. Despite increasing concerns regarding antiretroviral resistance, the death rate among HIV-infected persons in our cohort continues to decline. Our data show a lower death rate than that reported among many other US HIV-infected populations; this may be the result of open access to health care. A shift in the causes of death toward non-HIV-related causes suggests that a more comprehensive health care approach may be needed for optimal life expectancy; this may include enhanced screening for malignancy and heart disease as well as preventive measures for liver disease and accidents.

Decline in the AIDS and death rates in the EuroSIDA study: an observational study

Since the introduction of highly active antiretroviral therapy (HAART), little is known about whether changes in HIV-1 mortality and morbidity rates have been sustained. We aimed to assess possible changes in these rates across Europe. We analysed data for 9803 patients in 70 European HIV centres including ones in Israel and Argentina. Incidence rates of AIDS or death were calculated for overall and most recent CD4 count in 6-monthly periods and in three treatment eras (pre-HAART, 1994-1995; early-HAART, 1996-1997; and late-HAART, 1998-2002). The incidence of AIDS or death fell after September, 1998, by 8% per 6-month period (rate ratio 0.92, 95% CI 0.88-0.95, p<0.0001). When AIDS and death were analysed separately, the incidence of all deaths during the late-HAART era was significantly lower than that during the early-HAART era in patients whose latest CD4 count was 20 cells/microL or less (0.43, 0.35-0.53, p<0.0001), but at higher CD4 counts, did not differ between early-HAART and late-HAART. Incidence of AIDS was about 50% lower in late-HAART than in early-HAART, irrespective of latest CD4 count (p<0.0001). In multivariate Cox's models, with early-HAART as the reference, there was an increased risk of AIDS (relative hazard 1.39; 95% CI 1.16-1.67, p=0.0004) and all deaths (1.29; 1.08-1.56, p=0.0065) in the pre-HAART era, and a reduced risk of AIDS (0.62; 0.50-0.77, p<0.0001) and all deaths (0.66; 0.53-0.82, p=0.0002) in the late-HAART era. The initial drop in mortality and morbidity after the introduction of HAART has been sustained. Potential long-term adverse effects associated with HAART have not altered its effectiveness in treating AIDS.