Immunological similarities have been noted between HIV-infected individuals and older HIV-negative adults. Immunologic alterations with aging have been noted in frailty in older adults, a clinical syndrome of high risk for mortality and other adverse outcomes. Using a frailty-related phenotype (FRP), we investigated in the Multicenter AIDS Cohort Study (MACS) whether progressive deterioration of the immune system among HIV positive individuals independently predicts onset of FRP.
FRP was evaluated semiannually in 1,046 HIV-infected men from 1994–2005. CD4 T-cell count and plasma viral load were evaluated as predictors of FRP by logistic regression (GEE), adjusting for age, ethnicity, educational level, AIDS status, and treatment era (pre-HAART (1994–1995) and HAART (1996–1999 and 2000–2005)).
Adjusted prevalences of FRP remained low for CD4 T-cell counts >400 cells/mm3 and increased exponentially and significantly for lower counts. Results were unaffected by treatment era. After 1996, CD4 cell T-count, but not plasma viral load, was independently associated with FRP.
CD4 T-cell count predicted the development of a frailty-related phenotype among HIV infected men, independent of HAART use. This suggests that compromise of the immune system in HIV-infected individuals contributes to the systemic physiologic dysfunction of frailty.
HIV; aging; frailty; CD4 T-cell count; Highly active antiretroviral therapy; prospective population-based cohort
Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of highly active antiretroviral therapy (HAART). The impact of CH-B on long-term HAART outcomes has not been fully characterized.
To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study (MACS) were retrospectively analyzed. Subjects were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS defining illnesses, CD4 rise, and HIV suppression was assessed using regression analysis.
Of 816 men followed for a median of 7 years on HAART, 350 were never HBV infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death (8.3/1000 person-years (PYs)). It was highest in those with CH-B (17/1000 PYs, 95% CI 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% CI 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared to those never infected (P=0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted HR 4.1, p=0.04). There was no significant difference in AIDS defining events, HIV RNA suppression, and CD4 increase.
In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.
hepatitis B; HIV; HAART; CD4; mortality; isolated core hepatitis B
The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain.
We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/μL before HAART initiation; ≥ viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50–1000 copies/mL.
One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/μL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P = 0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of ≤200 vs. >350 cells/μL was 10.7 (P = 0.013), and at CD4 cell count of 201–350 vs. >350 cells/μL was 8.54 (P = 0.014).
In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.
AIDS; CD4 cell count; death; viral load
Poor adherence to highly active antiretroviral therapy (HAART) may result in treatment failure and death. Most reports of the effect of adherence to HAART on mortality come from studies where special efforts are made to provide HAART under ideal conditions. However, there are few reports of the impact of non-adherence to HAART on mortality from community HIV/AIDS treatment and care programmes in developing countries. We therefore conducted a study to assess the effect of adherence to HAART on survival in The AIDS Support Organization (TASO) community HAART programme in Kampala, Uganda.
The study was a retrospective cohort of 897 patients who initiated HAART at TASO clinic, Kampala, between May 2004 and December 2006. A total of 7,856 adherence assessments were performed on the data. Adherence was assessed using a combination of self-report and pill count methods. Patients who took ≤ 95% of their regimens were classified as non-adherent. The data was stratified at a CD4 count of 50 cells/mm3. Kaplan Meier curves and Cox proportional hazards regression models were used in the analysis.
A total of 701 (78.2%) patients had a mean adherence to ART of > 95%. The crude death rate was 12.2 deaths per 100 patient-years, with a rate of 42.5 deaths per 100 patient-years for non-adherent patients and 6.1 deaths per 100 patient-years for adherent patients. Non-adherence to ART was significantly associated with mortality. Patients with a CD4 count of less than 50 cells/mm3 had a higher mortality (HR = 4.3; 95% CI: 2.22–5.56) compared to patients with a CD4 count equal to or greater than 50 cells/mm3 (HR = 2.4; 95% CI: 1.79–2.38).
Our study showed that good adherence and improved survival are feasible in community HIV/AIDS programmes such as that of TASO, Uganda. However, there is need to support community HAART programmes to overcome the challenges of funding to provide sustainable supplies particularly of antiretroviral drugs; provision of high quality clinical and laboratory support; and achieving a balance between expansion and quality of services. Measures for the early identification and treatment of HIV infected people including home-based VCT and HAART should be strengthened.
Pregnancy has been associated with a decreased risk of HIV disease progression in the highly active antiretroviral therapy (HAART) era. The effect of timing of HAART initiation relative to pregnancy on maternal virologic, immunologic and clinical outcomes has not been assessed.
We conducted a retrospective cohort study from 1997–2005 among 112 pregnant HIV-infected women who started HAART before (N = 12), during (N = 70) or after pregnancy (N = 30).
Women initiating HAART before pregnancy had lower CD4+ nadir and higher baseline HIV-1 RNA. Women initiating HAART after pregnancy were more likely to receive triple-nucleoside reverse transcriptase inhibitors. Multivariable analyses adjusted for baseline CD4+ lymphocytes, baseline HIV-1 RNA, age, race, CD4+ lymphocyte count nadir, history of ADE, prior use of non-HAART ART, type of HAART regimen, prior pregnancies, and date of HAART start. In these models, women initiating HAART during pregnancy had better 6-month HIV-1 RNA and CD4+ changes than those initiating HAART after pregnancy (−0.35 vs. 0.10 log10 copies/mL, P = 0.03 and 183.8 vs. −70.8 cells/mm3, P = 0.03, respectively) but similar to those initiating HAART before pregnancy (−0.32 log10 copies/mL, P = 0.96 and 155.8 cells/mm3, P = 0.81, respectively). There were 3 (25%) AIDS-defining events or deaths in women initiating HAART before pregnancy, 3 (4%) in those initiating HAART during pregnancy, and 5 (17%) in those initiating after pregnancy (P = 0.01). There were no statistical differences in rates of HIV disease progression between groups.
HAART initiation during pregnancy was associated with better immunologic and virologic responses than initiation after pregnancy.
Lower percentages of CD4+ T lymphocytes are associated with adverse clinical outcomes among children and adolescents infected with human immunodeficiency virus (HIV). CD4+ lymphocyte percentage generally increases with receipt of highly active antiretroviral therapy (HAART), but long-term follow-up is required to assess whether these increases in CD4+ cell percentage are maintained and whether they lead to normal CD4+ cell percentages in children with severe immunosuppression.
The study population included 1236 children and adolescents perinatally infected with HIV who were enrolled in a US-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C) and who were not receiving HAART at study initiation. We estimated the effects of HAART, HAART with protease inhibitors, and HAART with nonnucleoside reverse-transcriptase inhibitors on CD4+ cell percentage, using marginal structural models to account for confounding by severity.
Initiation of any type of HAART increased CD4+ cell percentage by 2.34% (95% confidence interval, 1.35%–3.33%) in the first year, relative to noninitiation of HAART. The substantial increases in CD4+ cell percentage observed after the first year of experience with these combination therapies were followed by relatively smaller increases that continued for 5 years after initiation. Although larger increases in CD4+ cell percentage were observed among children with a greater degree of immunosuppression at baseline, the mean CD4+ cell percentage after 5 years of HAART did not reach normal levels.
Our study supports the initiation of HAART in children before severe immunosuppression occurs for long-term maintenance of normal CD4+ cell percentages. This beneficial result must be weighed against the evidence of potential adverse events associated with the prolonged use of such therapy.
Little is known about modifications to highly active antiretroviral therapy (HAART) initiated during acute or early HIV infection.
Reasons for first modifications of HAART regimens were recorded using the AIDS Clinical Trials Group form among 363 subjects who initiated HAART within 1 year of seroconversion from 2005 in the Acute Infection and Early Disease Research Program. Modifications recorded as due to “patient choice” or “physician choice” were clarified by query to the recording site. Times to events were analyzed by Kaplan–Meier methods; significance of differences was assessed by the log-rank test.
Two hundred five of 363 (56%) subjects modified therapy, at a median of 425 days after initiation, by changing drugs, discontinuing treatment, or removing or adding drugs. Most modifications were attributed to toxicity (n = 105, 51%), most of which was low grade; regimen simplification (n = 18, 5%); and achievement of viral suppression (n = 15, 7%). Time to first modification was shorter for those with shorter time from infection to initiation (P = 0.005) and those having higher CD4 lymphocyte count at initiation (P = 0.06). Modifications occurred sooner in subjects receiving regimens taken more than once daily (P < 0.001) or with more than 2 pills daily (P < 0.001). Most regimens were nonnucleoside reverse transcriptase inhibitor based or protease inhibitor based, and these did not differ significantly in rate and timing of modification.
HAART initiated early in HIV infection was modified in the majority of cases, usually due to minor toxicities whose incidence was similar for protease inhibitor–based and nonnucleoside reverse transcriptase inhibitor–based regimens. Convenience of regimens (lower pill burden and dosing frequency) was associated with a lower rate of modification.
cohort studies; regimen modification; toxicity
While highly active antiretroviral therapy (HAART) decreases long-term morbidity and mortality, its short-term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders.
Hospitalizations among 1327 HAART-naïve subjects in an urban HIV clinic in 1997–2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (≥ 1 log10 decrease in HIV-1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD-9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization.
During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre-HAART baseline rate [75.1 vs. 78.8/100 person-years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections.
The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time.
AIDS-defining illness; antiretroviral therapy; healthcare utilization; hospitalization; immune reconstitution
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
To examine the outcomes of highly-active antiretroviral therapy (HAART) for individuals with free access to healthcare, we evaluated 2327 patients in a cohort study composed of military personnel and beneficiaries with HIV infection who initiated HAART from 1996 to the end of 2007.
Outcomes analyzed were virologic suppression (VS) and failure (VF), CD4 count changes, AIDS and death. VF was defined as never suppressing or having at least one rebound event. Multivariate (MV) analyses stratified by the HAART initiation year (before or after 2000) were performed to identify risk factors associated with these outcomes.
Among patients who started HAART after 2000, 81% had VS at 1 year (N = 1,759), 85% at 5 years (N = 1,061), and 82% at 8 years (N = 735). Five years post-HAART, the median CD4 increase was 247 cells/ml and 34% experienced VF. AIDS and mortality rates at 5 years were 2% and 0.3%, respectively. In a MV model adjusted for known risk factors associated with treatment response, being on active duty (versus retired) at HAART initiation was associated with a decreased risk of AIDS (HR = 0.6, 95% CI 0.4-1.0) and mortality (0.6, 0.3-0.9), an increased probability of CD4 increase ≥ 50% (1.2, 1.0-1.4), but was not significant for VF.
In this observational cohort, VS rates approach those described in clinical trials. Initiating HAART on active duty was associated with even better outcomes. These findings support the notion that free access to healthcare likely improves the response to HAART thereby reducing HIV-related morbidity and mortality.
Although a decrease in acquired immunodeficiency syndrome (AIDS)-related mortality has been documented in highly active antiretroviral therapy (HAART) era, there are no published data comparing specific causes of death between pre-HAART and HAART era in Korea. Mortality and cause of death were analyzed in three treatment periods; pre-HAART (1990-1997), early-HAART (1998-2001), and late-HAART period (2002-2011). The patients were retrospectively classified according to the treatment period in which they were recruited. Although mortality rate per 100 person-year declined from 8.7 in pre-HAART to 4.9 in late-HAART period, the proportion of deaths within 3 months of initial visit to study hospital significantly increased from 15.9% in pre-HAART to 55.1% in late-HAART period (P < 0.001). Overall, 59% of deaths were attributable to AIDS-related conditions, and Pneumocystis pneumonia (PCP) was the most common cause of death (20.3%). The proportion of PCP as cause of death significantly increased from 8.7% in pre-HAART to 31.8% in late-HAART period (P < 0.001). Despite of significant improvement of survival, there was still a high risk of early death in patients presenting in HAART era, mainly due to late human immunodeficiency virus (HIV) diagnosis and late presentation to care.
HIV; Antiretroviral Therapy; Mortality; Cause of Death
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
Treatment with highly active antiretroviral therapy (HAART) reduces overall perinatal HIV-1 related mortality. The impact of timing of HAART initiation on reduction of morbidity is not well-defined. We evaluated the association of timing of HAART initiation on progression to moderate or severe disease.
Retrospective, population-based study of 196 perinatally HIV-infected children followed from birth in northern California from 1988 to 2009.
Of 196 children, 58% received HAART and were followed for a median of 6.2 years after HAART initiation. HAART use was associated with improved survival to age 5 years: 50% no HAART vs. 88% HAART, p<0.0001. However, the advantage of initial HAART over mono or dual therapy transitioning to HAART was small and not statistically significant (p=0.23). Starting HAART before the development of moderate or severe disease delayed the median age of diagnosis of moderate disease from 0.4 years (IQR [0.3–0.8]) without HAART to 3.0 years ([IQR 1.9–5.8], p<.0001) with HAART. HAART initiation after progression to moderate or severe disease was associated with decreased progression to severe disease or death, respectively (moderate to severe: 8% (3/36) HAART vs. 84% (70/83) no HAART, p<0.0001; severe to death: 9% (6/68) HAART vs. 73% (49/67) no HAART, p<0.0001).
In perinatal HIV infection, HAART is associated with delayed progression and reduced mortality regardless of disease severity at HAART initiation. This finding reinforces U.S. guidelines regarding HAART initiation at>1 year of age if children present with most clinical category B diagnoses, regardless of CD4 measurements or plasma HIV RNA level.
perinatal; HIV-1; highly active antiretroviral therapy (HAART); timing of onset
Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts.
A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana's National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88–0.94 before tracing and 0.83 (95% confidence interval, 0.79–0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05–2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65–3.05)].
Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.
The prevalence of depression is elevated among HIV-infected individuals and there is evidence that depression exerts a negative impact on HIV medication adherence.
Merged HIV/AIDS surveillance data and Medicaid claims data from January 1996 to December 1998 were used to identify AIDS-infected patients with diagnosed depression, and filled prescriptions were used to identify their antidepressant use, and highly active antiretroviral therapy (HAART). Chi-square tests and robust logistic regressions were used to examine antidepressant use after HAART initiation, and a person-month approach was used to estimate the association between antidepressant treatment and adherence to HAART after its initiation.
Of the 406 AIDS-infected patients diagnosed with depression who initiated HAART during this period, 81% (N = 329) were treated with an antidepressant. The HAART adherence rate was low overall. After HAART initiation; only 63% of the person-months had a prescription for it. However, use of an antidepressant in the prior month was significantly associated with HAART in the current month. After controlling for other factors, the odds of current-month HAART adherence were increased by almost 30% for those with antidepressant use in the prior month (Adjusted OR = 1.28, 95% CI [1.16, 1.41]).
While the HAART adherence rate was low among patients with AIDS diagnosed with depression, prior month’s antidepressant use increases odds of adherence. Unmeasured factors may influence the reported association between antidepressant use and HAART adherence, but our findings point to the need to investigate directly the impact of antidepressant therapy on HAART adherence found among patients with AIDS and depression.
HIV; Adherence; Depression; Antidepressant
Highly active antiretroviral therapy (HAART) has changed the face of human immunodeficiency virus (HIV)
acquired immune deficiency syndrome (AIDS) by leading to dramatic decreases in HIV-related morbidity and
mortality in the developed as well as developing world. Since the introduction of HAART, the incidence of
ocular opportunistic infections causing retinitis has dramatically decreased, and clinicians should be aware
of changes in the clinical presentation of ocular manifestations of HIV. As studies of HIV disease after the
introduction of HAART continue to become available, more thorough descriptions of treated patients with
ocular opportunistic infections will include side-effects and toxicities of therapy. This review focuses on the
impact of HAART on the ocular manifestations of HIV.
Acquired immune deficiency syndrome; eye; highly active antiretroviral treatment; human immunodeficiency virus; India; ophthalmology; therapy
This retrospective cohort study of HIV-infected women receiving highly active antiretroviral therapy (HAART) while pregnant assessed the effect of postpartum HAART discontinuation on maternal AIDS-defining events (ADEs), non-AIDS–defining events (non-ADEs), and death 1997–2008 in Nashville, Tennessee. Cox proportional hazards models compared rates of ADE or all-cause death and non-ADE or all-cause death, and competing risks analyses compared rates of ADE or ADE-related death and non-ADE or non-ADE–related death across the groups. There were two groups: women who stopped HAART postpartum (discontinuation, n = 54) and women who continued HAART postpartum (continuation, n = 69). Fifty percent were African American, 40% had prior non-HAART antiretroviral therapy (ART) use, and 38% had a history of illicit drug use. Median age was 27.5 years, baseline CD4(%) was 532 (34%) and CD4 nadir was 332 cells/mm3, baseline and peak HIV-1 RNA were 2.6 and 4.32 log10 copies per milliliter, respectively. Women in the continuation group were older, had lower baseline CD4, CD4%, and CD4 nadir, and had higher peak HIV-1 RNA. In multivariable proportional hazards models, the hazard ratios [95% confidence interval (CI)] of ADE or all-cause death and non-ADE or all-cause death were lower in the continuation group, but not statistically significantly: 0.50 (0.12, 2.12; p = 0.35) and 0.69 (0.24, 1.95; p = 0.48), respectively. The results were similar in competing risks analyses. Despite having characteristics associated with worse prognosis, women who continued HAART postpartum had lower hazard ratio point estimates for ADEs or death and non-ADEs or death than women who discontinued HAART. Larger studies with longer follow-up are indicated to assess this association.
The heterogeneity of CD4+ T-cell counts and HIV-1 RNA at 5-12 years after the initiation of highly active antiretroviral therapy (HAART) remains largely uncharacterized.
In the Multicenter AIDS Cohort Study, 614 men who initiated HAART contributed data 5-12 years subsequently. Multivariate regression was used to evaluate the predictors of CD4+ counts and HIV-1 RNA levels.
At 5-12 years post-HAART, the median CD4+ T-cell count was 586 (inter quartile range (IQR): 421-791) cells/μl and 78% of the HIV-1 RNA measurements were undetectable. Higher CD4+ T-cell counts 5-12 years post-HAART were predicted by higher CD4+ T-cell counts and higher total lymphocyte count pre-HAART, lack of hepatitis B or C virus co-infections, and greater CD4+ T-cell change as well as suppressed HIV-1 RNA in the first 5 years after starting HAART. Older men (≥50 years) with 351-500 CD4+ cells/μl at HAART initiation had adjusted mean CD4+ T-cell count of 643 cells/μl at 10-12 years post-HAART, which was similar to the adjusted mean CD4+ T-cell count (670 cells/μl, p=0.45) in this period for younger men starting HAART with lower CD4+ T-cell counts. HIV-1 RNA suppression in the first 5 years post-HAART predicted subsequent viral suppression.
Immunological and virological responses in the first five years post-HAART predicted subsequent CD4+ T-cell counts and HIV-1 RNA levels. The association between age and subsequent CD4+ T-cell count supports incorporating age in guidelines for use of HAART.
CD4+ T-cells; HIV-1 RNA; HAART; response; age effects
We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women’s Interagency HIV Study (WIHS) prior to the introduction of highly active antiretroviral therapy (HAART).
The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modeled using proportional hazards analysis.
Compared to the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly elevated for women with confirmed microalbuminuria (HR 1.9; 95% CI 1.2–2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3; 95% CI 1.3–4.3), while women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4; 95% CI 1.2–4.6).
In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, while pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population.
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
Cryptococcal meningitis (CM) is the proximate cause of death in 20–30% of persons with AIDS in Africa.
Two prospective observational cohorts enrolled HIV-infected, antiretroviral-naïve persons with CM in Kampala, Uganda; the first in 2001–02 (n=92) prior to HAART availability; the second in 2006–07 (n=44) with HAART available.
Ugandans presented with prolonged CM symptoms (median 14, IQR: 7 to 21 days). The 14-day survival was 49% (45/92) in 2001–02 and 80% (35/44) in 2006 (P<.001). HAART was started 35 ± 13 days from CM diagnosis and does not explain the improved 14-day survival in 2006. In 2006–07, survival continued to decline after hospitalization with only 57% (25/44) alive before initiating HAART. Probable cryptococcal-related immune reconstitution inflammatory syndrome (IRIS) occurred in 42% (10/24) with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and on HAART in 2007.
The median CSF opening pressure was 330mm H2O with 81% having elevated pressure (≥200mm). Only five patients consented to therapeutic lumbar punctures. Pressures >250mm trended towards higher mortality (Odds Ratio (OR)= 2.1; 95% CI: 0.9 to 5.2; P=.09). Initial CSF WBC <5 cells/mL was associated with failure of CSF sterilization (OR=17.3; 95% CI: 3.1 to 94.3; P<.001), and protein level <35mg/dL was associated with higher mortality (OR=2.0; 95% CI: 1.2 to 3.3; P=.007).
Significant CM mortality persists despite amphotericin and HIV therapy due to high mortality prior to HAART and to IRIS-related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.
HIV; AIDS; Cryptococcosis; Cryptococcal Meningitis; Amphotericin B; Sub-Saharan Africa; immune reconstitution inflammatory syndrome
For patients with HIV/AIDS, highly active antiretroviral therapy (HAART) is currently the only effective therapy for progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease caused by polyomavirus JC. Immune reconstitution inflammatory syndrome (IRIS) following initiation of HAART can cause paradoxical clinical deterioration in patients with established PML. Because the onset of PML follows soon after initiation of HAART in some cases (unmasking), we investigated the role IRIS plays in unmasked PML. We reviewed records of 20 PML cases seen from 1997–2006 at the UCSD HIV primary care clinic. Eight cases presented with PML symptoms within 6 months of initiating HAART (referred to hereafter as unmasked PML), six patients were diagnosed with PML before initiating HAART, and six were diagnosed more than 6 months after starting HAART. Patients with unmasked PML constituted forty percent of our series, had relatively long survival, and commonly (50%) had lesions exclusively in the posterior fossa, a localization not previously reported with such a high prevalence. Only 3 of the 8 patients with unmasked PML had IRIS reactions as evidenced by contrast enhancement around lesions on MRI, suggesting that IRIS is not necessary for the pathogenesis of this syndrome.
HIV; PML; HAART; IRIS; immune reconstitution
The increasing use of highly active antiretroviral therapies (HAARTs) has changed the course of AIDS-related illnesses and enhanced the quality of life of patients infected with human immunodeficiency virus (HIV) and may have changes the causes of deaths in patients with acquired immunodeficiency syndrome (AIDS).
The aim of the present study was to investigate causes of deaths in long-term care hospital patients with late-stage AIDS who expired at the Coler-Goldwater Memorial Hospital in New York City in 1995, and in 1998 and 1999, that is, immediately before and the two most recent years after the advent of HAART.
Analysis of causes of deaths as recorded on the death certificates of 232 AIDS patients.
The overall mortality rate declined from 75.6 deaths per 100 person-years in 1995 to 33.2 deaths per 100 person-years in 1998–1999 (P<.001) The number of AIDS patients who expired because of sepsis and opportunistic infections, which includedPneumocystis carinii Pneumonia (PCP), decreased significantly from 30 (26.1%) and 24 (20.9%) in 1995 to 15 (12.8%) and 10 (8.5%) in 1998–1999, respectively (P<.05). In contrast, deaths from hepatic failure increased from 0(0%) in 1995 to 7 (6%) in 1998–1999 (P<.05). Increases, although not significant statistically, were associated with pneumonias excluding PCP, end-stage AIDS, renal failure, and malignancies. Analysis of cause-specific mortality by gender between 1995 and 1998–1999 revealed very little difference between men and women. This analysis showed, however, that the infectious processes taken together (pneumonias excluding PCP, sepsis, and opportunistic infections including PCP) were significantly less frequent causes of death in 1998–1999 than in 1995 (P<.01).
These findings indicate that HAART affected the causes of deaths in patients with AIDS, with “traditional” opportunistic infections diminishing in importance relative to chronic medical conditions and malignancies.
Death; HAART; Hepatic Failure; Late-Stage AIDS; Opportunistic Infections; Sepsis
Body mass index (BMI), waist circumference (WC) and neck circumference (NC) are important screening tools for sleep disordered breathing (SDB). However, the utility of anthropometry for this purpose has not been evaluated among HIV-infected patients.
HIV-uninfected men (HIV−; n=60), HIV-infected men receiving highly active antiretroviral therapy (HIV+/HAART; n=58), and HIV-infected men not receiving HAART (HIV+/No HAART; n=41) from the Multicenter AIDS Cohort Study underwent a nocturnal sleep study and anthropomorphic assessment. Moderate-severe SDB was defined as an apnea/hypopnea event rate ≥15 episodes/hour. Receiver operating characteristic (ROC) curves were used to compare the ability of different anthropometric measurements to predict SDB within each group.
Moderate-severe SDB was found in 48% (HIV−:57%; HIV+/HAART: 41%; HIV+/No HAART−: 44%). The performance of BMI, WC, and NC to predict SDB was excellent among the HIV− men (ROC areas-under-the curve (AUC): 0.83, 0.88, 0.88, respectively) and fair among the HIV+/HAART group (AUCs: 0.71, 0.77, 0.77, respectively). In contrast, these measurements had no predictive value in the HIV+/No HAART group (AUCs: 0.43, 0.41, 0.45, respectively). Moreover, in the HIV+/No HAART group, moderate-severe SDB was independently associated with serum C-reactive protein ≥3.0 mg/L (Odds Ratio (OR) 6.9; p=0.04) and HIV RNA > 10,000 copies/ml (OR 7.1; p=0.05).
BMI, waist circumference, and neck circumference had better predictive value for moderate-severe SDB in HIV-uninfected men compared to HIV-infected men, and had no value among HIV-infected men not receiving HAART. Among this latter group, systemic inflammation may contribute to the pathogenesis of SDB.
obstructive sleep apnea; HIV; lipodystrophy; anthropometry; body composition; sleep disordered breathing
Inadequate adherence to highly active antiretroviral therapy (HAART) may lead to poor health outcomes and the development of HIV strains that are resistant to HAART. We developed a model to evaluate the cost effectiveness of counseling interventions to improve adherence to HAART among men who have sex with men (MSM).
We developed a dynamic compartmental model that incorporates HIV treatment, adherence to treatment, and infection transmission and progression. All data estimates were obtained from secondary sources. We evaluated a counseling intervention given prior to initiation of HAART and before all changes in drug regimens, combined with phone-in support while on HAART. We considered a moderate-prevalence and a high-prevalence population of MSM.
If the impact of HIV transmission is ignored, the counseling intervention has a cost-effectiveness ratio of $25,500 per QALY gained. When HIV transmission is included, the cost-effectiveness ratio is much lower: $7,400 and $8,700 per QALY gained in the moderate- and high-prevalence populations, respectively. When the intervention is twice as costly per counseling session and half as effective as we estimated (in terms of the number of individuals who become highly adherent, and who remain highly adherent), then the intervention costs $17,100 and $19,600 per QALY gained in the two populations, respectively.
Counseling to improve adherence to HAART increased length of life, modestly reduced HIV transmission, and cost substantially less than $50,000 per QALY gained over a wide range of assumptions, but did not reduce the proportion of drug-resistant strains. Such counseling provides only modest benefit as a tool for HIV prevention, but can provide significant benefit for individual patients at an affordable cost.
Cost Effectiveness; Adherence; HIV; Counseling; Computer Simulation
Brazil accounts for ∼70% of injection drug users (IDU) receiving HAART in low/middle income countries. We evaluated the impact of HAART availability/access on AIDS-related mortality among IDU versus men who have sex with men (MSM).
Nationwide analysis on Brazilian IDU and MSM diagnosed with AIDS in 2000-2006.
Four national information systems were linked and Cox regression was used to assess impact of HAART availability/access on differential AIDS-related mortality.
Among 28,426 patients, 6,777 died during 87,792 person-years of follow-up. Compared to MSM, IDU were significantly less likely to be receiving HAART, to have ever had determinations for CD4 or viral load. After controlling for confounders, IDU had a significantly higher risk of death (AHR: 1.94; 95% CI: 1.84-2.05). Among the subset that had at least one CD4 and viral load determination, higher risk of death among IDU persisted (HR: 1.82; 95% CI: 1.58-2.11). Non-white ethnicity significantly increased this risk, while prompt HAART uptake after AIDS diagnosis reduced the risk of death. After controlling for spatially-correlated survival data, AIDS-related mortality remained higher in IDU than in MSM.
Despite free/universal HAART access, differential AIDS-related mortality exists in Brazil. Efforts are needed to identify and eliminate these health disparities.
HIV; AIDS; Survival; HAART; drug user