Agnes Kiragga

Cause-Specific Mortality and the Contribution of Immune Reconstitution Inflammatory Syndrome in the First 3 Years after Antiretroviral Therapy Initiation in an Urban African Cohort

BACKGROUND Although many studies have reported high early mortality among patients enrolled in antiretroviral therapy (ART) programs in sub-Saharan Africa-particularly among those individuals with advanced immunodeficiency-few studies have reported the most common causes of these early deaths. METHODS We determined cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome (IRIS) in a well-characterized patient cohort in Kampala, Uganda, over a 36-month period of ART. RESULTS In a cohort of patients who initiated antiretroviral therapy in Uganda, we observed a high early mortality rate among patients with advanced disease. The most common causes of death were tuberculosis and cryptococcal meningitis. The contribution of immune reconstitution inflammatory syndrome to mortality was limited. CONCLUSIONS We show a significant early mortality in our ART cohort in resource-limited settings that is driven by advanced human immunodeficiency virus disease and characterized by low CD4 cell counts. In our experience, the contribution of IRIS to this observed early mortality is limited.

High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort

BackgroundAntiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated.MethodsT-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199) cells/μl], N = 34 ], optimal [282 (200-415) cells/μl, N = 64] and super-optimal [528 (416-878) cells/μl, N = 30].ResultsBoth CD4+ and CD8 T-cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, P = 0.014)]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (P < 0.001) and super-optimal responders (P < 0.001). T-cell exhaustion was significantly associated with suboptimal responders [AOR, 1.5 (95%CI, 1.1-2.1), P = 0.022].ConclusionT-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.

Incident tuberculosis during antiretroviral therapy contributes to suboptimal immune reconstitution in a large urban HIV clinic in sub-Saharan Africa.

Background Antiretroviral therapy (ART) effectively decreases tuberculosis (TB) incidence long-term, but is associated with high TB incidence rates in the first 6 months. We sought to determine the incidence and the long-term effects of TB during ART on HIV treatment outcome, and the risk factors for incident TB during ART in a large urban HIV clinic in Uganda. Methodology/Principal Findings Routinely collected longitudinal clinical data from all patients initiated on first-line ART was retrospectively analysed. 5,982 patients were included with a median baseline CD4+ T cell count (CD4 count) of 117 cells/mm3 (interquartile range [IQR]; 42, 182). In the first 2 years, there were 336 (5.6%) incident TB events in 10,710 person-years (py) of follow-up (3.14 cases/100pyar [95% CI 2.82–3.49]); incidence rates at 0–3, 3–6, 6–12 and 12–24 months were 11.25 (9.58–13.21), 6.27 (4.99–7.87), 2.47 (1.87–3.36) and 1.02 (0.80–1.31), respectively. Incident TB during ART was independently associated with baseline CD4 count of <50 cells/mm3 (hazard ratio [HR] 1.84 [1.25–2.70], P = 0.002) and male gender (HR 1.68 [1.34–2.11], P<0.001). After two years on ART, the patients who had developed TB in the first 12 months had a significantly lower median CD4 count increase (184 cells/mm3 [IQR; 107, 258, n = 118] vs 209 cells/mm3 [124, 309, n = 2166], P = 0.01), a larger proportion of suboptimal immune reconstitution according to two definitions (increase in CD4 count <200 cells/mm3: 57.4% vs 46.9%, P = 0.03, and absolute CD4 count <200 cells/mm3: 30.4 vs 19.9%, P = 0.006), and a higher percentage of immunological failure according to the WHO criteria (13.6% vs 6.5%, P = 0.003). Incident TB during ART was independently associated with poor CD4 count recovery and fulfilling WHO immunogical failure definitions. Conclusions/Significance Incident TB during ART occurs most often within 3 months and in patients with CD4 counts less than 50 cells/mm3. Incident TB during ART is associated with long-term impairment in immune recovery.

Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance

BackgroundA proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, UgandaMethodsWe analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.ResultsOf 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].ConclusionUsing criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.

Cost Effectiveness of a Pharmacy-Only Refill Program in a Large Urban HIV/AIDS Clinic in Uganda

Background HIV/AIDS clinics in Uganda and other low-income countries face increasing numbers of patients and workforce shortages. We performed a cost-effectiveness analysis comparing a Pharmacy-only Refill Program (PRP), a form of task-shifting, to the Standard of Care (SOC) at a large HIV/AIDS clinic in Uganda, the Infectious Diseases Institute (IDI). The PRP was started to reduce workforce shortages and optimize patient care by substituting pharmacy visits for SOC involving monthly physician visits for accessing antiretroviral medicines. Methodology/Principal Findings We used a retrospective cohort analysis to compare the effectiveness of the PRP compared to SOC. Effectiveness was defined as Favorable Immune Response (FIR), measured as having a CD4 lymphocyte count of over 500 cells/µl at follow-up. We used multivariate logistic regression to assess the difference in FIR between patients in the PRP and SOC. We incorporated estimates of effectiveness into an incremental cost-effectiveness analysis performed from a limited societal perspective. We estimated costs from previous studies at IDI and conducted univariate and probabilistic sensitivity analyses. We identified 829 patients, 578 in the PRP and 251 in SOC. After 12.8 months (PRP) and 15.1 months (SOC) of follow-up, 18.9% of patients had a FIR, 18.6% in the PRP and 19.6% in SOC. There was a non-significant 9% decrease in the odds of having a FIR for PRP compared to SOC after adjusting for other variables (OR 0.93, 95% CI 0.55–1.58). The PRP was less costly than the SOC (US

Baseline severe anaemia should not preclude use of zidovudine in antiretroviral-eligible patients in resource-limited settings

520 vs. 655 annually, respectively). The incremental cost-effectiveness ratio comparing PRP to SOC was US

Stavudine toxicity in women is the main reason for treatment change in a 3-year prospective cohort of adult patients started on first-line antiretroviral treatment in Uganda

13,500 per FIR. PRP remained cost-effective at univariate and probabilistic sensitivity analysis. Conclusion/Significance The PRP is more cost-effective than the standard of care. Similar task-shifting programs might help large HIV/AIDS clinics in Uganda and other low-income countries to cope with increasing numbers of patients seeking care.

Sexual behaviors over a 3-year period among individuals with advanced HIV/AIDS receiving antiretroviral therapy in an urban HIV clinic in Kampala, Uganda

BackgroundStavudine is no longer recommended as part of first-line therapy for patients initiating antiretroviral therapy (ART) in Uganda. Most patients are currently initiated on zidovudine-containing regimens, which can induce anaemia. We investigated the risk factors for early severe anaemia in the first six months of ART initiation.MethodsWe defined baseline (ART initiation) anaemia as haemoglobin (Hb) ≤9.5 g/dL, baseline severe anaemia as Hb ≤8 g/dL, and early severe anaemia as Hb ≤8 g/dL within six months of ART initiation. Risk factors for the development of early severe anaemia were analyzed using a multivariable logistic regression model.ResultsIn total, 5494 patients initiated ART, 821 (15%) had baseline anaemia, and 296 (5%) had baseline severe anaemia. Early severe anaemia occurred in 109 (4%) of 3105 patients who had at least one Hb measurement in the first six months on ART. Patients with baseline anaemia had a larger increase in Hb (median g/dL [IQR]) within the first six months compared with non-anaemic patients (2.9 [1.7, 4.6] vs. 0.7 [-0.2, 1.7], p < 0.0001). Having a new tuberculosis episode OR 3.69 (95% CI 1.64 - 8.32), MCV <80fL OR 1.60 (95% CI 1.01- 2.52) and baseline severe anaemia OR 5.27 (95% CI 3.00 - 9.26) were associated with early severe anaemia. Initiation on a zidovudine-based regimen was not associated with an increased risk of early severe anaemia.ConclusionsAmong patients in an urban HIV clinic in Uganda, severe anaemia is modestly prevalent at ART initiation and improves with ART in the majority of patients. These data suggest that baseline severe anaemia should not be used as a criterion for avoiding the use of zidovudine in patients initiating ART in resource-limited settings.

Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART-treated suboptimal immune responders in Uganda: a randomised crossover placebo-controlled trial.

Purpose:In resource-limited settings, there are only a few antiretroviral treatment (ART) options. Our objective was to evaluate the reasons for first-line ART changes in resource-limited settings. Methods:Prospective research cohort of patients initiating ART between April 2004 and April 2005 in Kampala, Uganda. The main endpoint was the substitution of at least 1 drug included in the initial combination. Results:Five hundred Fifty-nine patients initiated on ART, 70% were female, median CD4+ count 98 (21-163) cells per microliter, median HIV RNA log10 5.4 (5.0-5.8). 413 (74%) patients were started on stavudine, lamivudine, and nevirapine, and 146 (36%) on zidovudine, lamivudine and efavirenz. One hundred Forty-eight (26.5%) had at least one treatment change (incidence rate 14.3 per 100 person-years; confidence interval: 12.2 to 16.9). The main reason for first treatment change was drug toxicity (n = 91, 61.5%). Stavudine accounted for the majority of the toxicities that led to drug substitution (n = 76, 84%). In the multivariate analysis, being female (P = 0.011) and being stage 3-4 as compared with 1-2 at ART initiation were predictive of stavudine substitution (P = 0.05). There was no difference in virologic outcome in patients who changed due to toxicity compared with those who did not. Conclusions:The majority of the treatment changes were due to stavudine-related toxicity. Long-term stavudine use is less well tolerated in women.

Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa.

Background:Few studies have prospectively examined sexual behaviors of HIV-infected person on antiretroviral therapy (ART) in sub-Saharan Africa. Methods:Between 2004 and 2005, 559 HIV-infected, ART-naïve individuals initiating ART at an HIV clinic in Kampala, Uganda, were enrolled into a prospective study and followed to 2008. Clinical and sexual behavior information was assessed at enrollment and semiannually for 3 years after ART initiation. Using log-binomial regression models, we estimated prevalence ratios (PRs) to determine factors associated with being sexually active and having unprotected sex over 3 years after initiating ART. Results:Five hundred fifty-nine adults contributed 2594 person-visits of follow-up. At the time of ART initiation, 323 (57.9%) were sexually active of which 176 (54.5%) had unprotected sex at last sexual intercourse. The majority (63.4%) of married individuals were unaware of their partners HIV status. Female gender (PR, 2.97; 95% confidence interval, 1.85-4.79), being married (PR, 1.48; 95% confidence interval, 1.06-2.06), and reporting unprotected sex before ART (PR, 1.68; 95% confidence interval, 1.16-2.42) were among the factors independently associated with unprotected sex while on ART. Overall, 7.3% of visit intervals of unprotected sex, 1.0% of intervals of sexual activity, occurred when plasma viral load greater than 1500 copies/mL, representing periods of greater HIV transmission risk. Conclusions:Although unprotected sex reduced over time, women reported unprotected sex more often than men. Disclosure of HIV status was low. Integration of comprehensive prevention programs into HIV care is needed, particularly ones specific for women.