To evaluate the short- and long-term effects of highly active antiretroviral therapy (HAART) on tuberculosis (TB) risk, compared to risk without HAART in a low TB incidence setting.
An observational cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between January 1998 and December 2008.
A marginal structural model was used to estimate the effect of HAART on short- (≤180 days) and long-term (>180 days) TB risk, with CD4+ lymphocyte count incorporated as a time-updated covariate.
Of 4,534 HIV-infected patients, 34 developed TB (165/100,000 p-y; 20,581 person-years [p-y] of follow-up). Seventeen cases occurred among persons not on HAART or >30 days after HAART discontinuation (212/100,000 p-y; 8,019 p-y of follow-up). Seventeen occurred among persons on HAART (135/100,000 p-y; 12,562 p-y of follow-up); ten in the first 180 days (402/100,000 p-y; 2,489 p-y of follow-up) and 7 after more than 180 days (69/100,000 p-y; 10,073 p-y of follow-up). After adjusting for the most recent CD4+ lymphocyte count, the risk of TB in the first 180 days of HAART exposure relative to no HAART was 0.68 (0.14–3.22, p=0.63).
In this low TB incidence setting, the TB rate in the first 180 days of HAART was almost twice as high as persons not on HAART. However, after adjusting for most recent CD4+ count there was no significant difference in TB risk between these two groups. This suggests that low recent CD4+ lymphocyte count influences TB risk during the first 180 days of HAART.
tuberculosis; M. tuberculosis infection; tuberculosis risk; human immunodeficiency virus; highly active antiretroviral therapy
Although highly active antiretroviral therapy (HAART) reduces mortality in the developed world, it remains undocumented in resource-poor settings. We assessed the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in Ethiopia. The objective of this study was to assess the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in a resource-limited setting in south Ethiopia. Starting in January 2003, we followed all consecutive adult HIV infected patients who visited the HIV clinic. Since August 2003, we treated patients with HAART. Only basic laboratory services were available.
We followed 185 patients in the pre-HAART cohort and 180 patients in the HAART cohort. The mortality rate was 15.4 per 100 person-years of observation (PYO) in the HAART group and tuberculosis incidence rate was 3.7 per 100 PYO. In the pre-HAART group, the mortality rate was 58.1 per 100 PYO and the tuberculosis incidence rate was 11.1 per 100 PYO. HAART resulted in a 65% decline in mortality (adjusted hazard ratio [95%CI] = 0.35 [0.19–0.63]; P < 0.001). Tuberculosis incidence rate was lower in the HAART group (adjusted hazard ratio [95%CI] = 0.11 [0.03–0.48]; P < 0.01). Most of the deaths occurred during the first three months of treatment.
HAART improved survival and decreased tuberculosis incidence to a level similar to that achieved in the developed countries during the early years of HAART. However, both the mortality and the tuberculosis incidence rate were much higher in terms of absolute figures in this resource-limited setting. Attention should be paid to the early weeks of treatment when mortality is high. The high tuberculosis incidence rate, when coupled with the improved survival, may lead to increased tuberculosis transmission. This highlights the need for strengthening tuberculosis prevention efforts with the scale-up of treatment programmes
Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART.
We evaluated a cohort of 7,066 patients who initiated HAART between April 2004 and March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation; concurrent initiation of TB treatment and HAART; incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks.
Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dose. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI] 1.82-5.56) in the first two months of HAART, 2.51 (95% CI 1.77-3.54) in months 3-6, and 1.19 (95% CI 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI 3.03-14.37) in the first two months,1.88 (95% CI 0.87-4.09) in months 3-6, and 1.07 (95% CI 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk.
Risk of stavudine substitution was increased among patients receiving TB treatment, especially soon after HAART initiation. In settings where alternative antiretroviral drugs are available, initiation of stavudine in patients receiving TB treatment may need to be reconsidered.
Tuberculosis treatment; HIV; stavudine; highly active antiretroviral therapy (HAART); drug interactions
Human Immunodeficiency Virus (HIV) infection predisposes to tuberculosis (TB). We described incidence, risk factors and prognosis of TB in HIV-1 infected patients during pre (1995-1996), early (1997-1999), and late Highly Active Antiretroviral Therapy (HAART) (2000-2007) periods.
We included patients from a population-based, multicenter, nationwide cohort. We calculated incidence rates (IRs) and mortality rates (MRs). Cox's regression analysis was used to estimate risk factors for TB infection with HAART initiation included as time updated variable. Kaplan-Meier was used to estimate mortality after TB.
Among 2,668 patients identified, 120 patients developed TB during the follow-up period. The overall IR was 8.2 cases of TB/1,000 person-years of follow-up (PYR). IRs decreased during the pre-, early and late-HAART periods (37.1/1000 PYR, 12.9/1000 PYR and 6.5/1000 PYR respectively). African and Asian origin, low CD4 cell count and heterosexual and injection drug user route of HIV transmission were risk factors for TB and start of HAART reduced the risk substantially. The overall MR in TB patients was 34.4 deaths per 1,000 PYR (95% Confidence Interval: 22.0-54.0) and was highest in the first two years after the diagnosis of TB.
Incidence of TB still associated with conventional risk factors as country of birth, low CD4 count and route of HIV infection while HAART reduces the risk substantially. The mortality in this patient population is high in the first two years after TB diagnosis.
The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa.
Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk.
Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78).
Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.
HAART; isoniazid; preventive treatment; sub-Saharan Africa; tuberculosis
The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART.
We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005.
Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%).
We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.
For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events.
In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART.
A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar.
Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability.
Antiretroviral; Early; Delayed; HIV; Tuberculosis
The development of jaundice after initiation of HAART in HIV-TB co-infected patients is a challenging presentation in resource constrained settings, and is often attributed to drug induced liver injury (DILI).Some investigators have described hepatic tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) as a cause of liver disease in patients initiating HAART, which could also cause jaundice.
We report the clinical and histopathological features of five HIV-TB co-infected patients presenting with a syndrome of jaundice, tender hepatomegaly, bile canalicular enzyme rise and return of constitutional symptoms within 8 weeks of initiation of highly active antiretroviral therapy (HAART) for advanced HIV infection at a rural clinic in KwaZulu Natal, South Africa.
All five patients had been diagnosed with tuberculosis infection prior to HAART initiation and were on antituberculous medication at time of developing jaundice. There was evidence of multiple aetiologies of liver injury in all patients. However, based on clinical course and pathological findings, predominant hepatic injury was thought to be drug induced in one case and hepatic tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in the other four.
In these later 4 patients, liver biopsy findings included necrotising and non-necrotising granulomatous inflammation in the lobules and portal tracts. The granulomas demonstrated – in addition to epithelioid histiocytes and Langhans giant cells – neutrophils, plasma cells and large numbers of lymphocytes, which are not features of a conventional untreated tuberculous response.
In this high TB prevalent, low resource setting, TB-IRIS may be an important cause of jaundice post-HAART initiation. Clinicopathological correlation is essential for optimal diagnosis. Further multi-organ based histopathological studies in the context of immune reconstitution would be useful to clinicians in low resource settings dealing with this challenging presentation.
Human immunodeficiency virus; Tuberculosis; Immune reconstitution inflammatory syndrome; Drug induced liver injury; Jaundice; Low resource setting; Liver biopsy
Rationale: In 2005, we reported high prevalence of untreated pulmonary tuberculosis (TB) in a South African community. Prevalent untreated TB is the main source of transmission. In settings with large burdens of human immunodeficiency virus (HIV) and TB, highly active antiretroviral therapy (HAART) may contribute to TB control.
Objectives: To assess the community-level impact of HAART on TB prevalence, we repeated a community-based TB prevalence cross-sectional survey in 2008 following HAART roll-out.
Methods: A random 10% adult population sample was identified from the community. Participants provided two sputum specimens for acid-fast bacilli microscopy and TB culture. Oral transudate specimen was collected for anonymous HIV testing, linked to TB diagnosis. An interviewer-administered, structured questionnaire identified TB and HIV history and risk factors.
Measurements and Main Results: In the 2008 survey, 1,250 adults participated (90% response rate); 306 (25%) tested HIV positive, of which 60 (20%) were receiving HAART. A total of 20 TB cases were identified (12 receiving TB treatment), representing a significant decline in prevalence from 3.2 to 1.6% (P = 0.02) between the surveys. TB prevalence in participants not infected with HIV was unchanged (P = 0.90). The decline occurred among participants not infected with HIV, decreasing from 9.2 to 3.6% in 2005 to 2008, respectively (P = 0.003). In participants infected with HIV, prevalence of treated TB declined from 4 to 2.3% (P = 0.06), and untreated TB prevalence from 5.2 to 1.3% (P = 0.02). The proportion of untreated TB in patients receiving HAART decreased significantly, from 22 to 0% (P < 0.001).
Conclusions: Prevalence of undiagnosed TB declined significantly over a period of increasing HAART availability. The decline was predominantly in individuals infected with HIV receiving HAART.
tuberculosis; prevalence; human immunodeficiency virus; antiretroviral therapy
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
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 absence of highly active therapy antiretroviral (HAART), adults with AIDS experience substantially elevated influenza-associated mortality in South Africa and the United States. This elevated mortality risk declined with widespread HAART introduction in the United States but did not disappear entirely. These data support increased access to HAART and influenza vaccination for human immunodeficiency virus–infected adults globally.
Background. Data are limited on human immunodeficiency virus (HIV)–associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States.
Methods. Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25–54 years in South Africa (1998–2005) and the United States (pre-HAART era, 1987–1994; HAART era, 1997–2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults ≥65 years old.
Results. In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49–460) and 208 (95% CI, 74–583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9–7.2) and 4.1 (95% CI, 1.4–13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16–121]); P&I RR, 73 [95% CI, 47–113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era.
Conclusions. Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults.
The effect of tuberculosis on mortality in people initiating highly active antiretroviral treatment (HAART) remains unclear; here, we strengthened a previous cohort analysis. Multivariate Cox proportional hazards models were used to assess the association of baseline tuberculosis and time to all-cause mortality among HAART initiators. In reanalysis, treatment for tuberculosis at time of HAART initiation remained unassociated with increased risks of all-cause mortality, with adjusted hazard ratios ranging from 1.00 to 1.09.
Immune reconstitution inflammatory syndrome (IRIS) after initiating highly active antiretroviral therapy (HAART) has not been widely studied in children, especially in resource-poor settings.
Retrospective cohort study of HIV-infected children initiating HAART between 2001 and 2006 at a tertiary pediatric hospital in Lima, Peru. Charts were reviewed for 1 year after HAART initiation. IRIS was defined as a HAART-associated adverse event caused by an infectious or inflammatory condition in patients with documented virologic or immunologic success.
Ninety-one children (52% female) received HAART for at least 1 year. Median age at initiation was 5.7 years; 91% were ART naive and 73% had CDC stage C disease. The incidence of IRIS was 19.8 events per 100 person years (95% CI: 11.5–28.0). Median time to IRIS was 6.6 weeks after HAART initiation (range: 2–32 weeks). There were 18 IRIS events, 11 unmasking and 7 paradoxical. These included associations with Mycobacterium tuberculosis in 4 cases, Bacillus Calmette Guerin lymphadenitis in 1 case, varicella zoster virus in 6 cases and herpes simplex labialis in 6 cases. Children who developed IRIS had a higher baseline HIV viral load (P = 0.02) and an indicator of malnutrition (P = 0.007) before HAART initiation.
IRIS occurred in 20% of HIV-infected children starting HAART in Peru and was associated with more advanced disease and malnutrition. Future research is needed to examine specific risk factors associated with pediatric IRIS to allow prompt identification and treatment of IRIS.
immune reconstitution inflammatory syndrome; HIV; AIDS; HAART; children
In the United States, women, racial/ethnic minorities and persons who acquire HIV infection through heterosexual intercourse represent an increasing proportion of HIV infected persons, yet are frequently underrepresented in clinical trials. We assessed the demographic predictors of trial participation in antiretroviral naïve patients.
Patients were characterized as trial participants if highly-active antiretroviral therapy (HAART) was initiated within a clinical trial. Prevalence ratios (PR) were obtained using binomial regression.
Between 1996–2006, 30% of 738 treatment naïve patients initiated HAART in a clinical trial. Trial participation rates for MSM, heterosexual men, and women were respectively 36.5%, 29.6% and 24.3%. After adjustment for other factors, heterosexual men appeared less likely to participate in trials compared to MSM (PR: 0.79, 95%CI 0.57, 1.11) while women were as likely to participate as MSM (PR 0.97, 95%CI 0.68, 1.39). The participation rate in blacks (25.9%) was lower compared to non-blacks (37.5%) (adjusted PR 0.80, 95%CI 0.60, 1.06).
In our clinical setting gender did not appear to impact participation in HIV treatment trials but blacks were slightly less likely to participate in these trials. Considering the substantial proportion of HIV patients who are black, future trials need to consider strategies to incorporate underrepresented populations.
HIV infection; clinical trials; highly active antiretroviral therapy; gender; sexual orientation; race
The incidence of tuberculosis in the United States, after decreasing for many years, has recently begun to climb at an alarming rate. This rise is due mainly to excess cases in high-risk groups including human immunodeficiency virus-infected patients, the elderly, the foreign born, and the homeless. In the United States tuberculosis has been associated with a 10% mortality despite adequate treatment. The tuberculin skin test is a safe and inexpensive test for detecting tuberculous infection. To improve its predictive value the diagnostic criteria for classifying a positive reaction have recently been revised. High-risk populations should be screened to identify those persons who would most benefit from preventive treatment. Isoniazid therapy taken for 6 to 12 months is a safe and highly effective means of preventing tuberculous infection from developing into active disease. The most worrisome toxicity of isoniazid, fatal hepatitis, is extremely rare; when patients are monitored closely the incidence of death from hepatotoxicity is less than 0.01%.
To examine the prevalence and biopsychosocial predictors of sub-optimal virologic response to highly active antiretroviral therapy (HAART) among human immunodeficiency virus (HIV)-infected adolescents.
Population-based cohort study.
Sixteen academic medical centers across thirteen cities in the United States.
One hundred and fifty four HIV-infected adolescents who presented for at least two consecutive visits after initiation of HAART.
Main Outcome Measures
Viral load (plasma concentration of HIV RNA), CD4+ T-lymphocyte count.
Of the 154 adolescents enrolled in the study, 50 (32.5%) demonstrated early and sustained virologic suppression while receiving HAART. The remaining 104 adolescents (67.5%) had a poor virologic response. Adequate adherence (>50%) to HAART—reported by 70.8% of respondents—was associated with a 60% reduced odds of suboptimal virologic suppression in a multivariable logistic regression model (adjusted odds ratio = 0.4; 95% confidence interval : 0.2 – 1.0). Exposure to sub-optimal antiretroviral therapy (ART) prior to HAART, on the other hand, was associated with more than a two-fold increased odds of sub-optimal virologic response (adjusted odds ratio = 2.6; 95% confidence interval: 1.1 – 5.7).
Fully two-thirds of HIV-infected adolescents in the current study demonstrated a sub-optimal virologic response to HAART. Non-adherence and prior single or dual ART were associated with subsequent poor virologic responses to HAART. These predictors of HAART failure echo findings in pediatric and adult populations. Given the unique developmental stage of adolescence, age-specific interventions are indicated to address high rates of non-adherence and therapeutic failure.
HIV; Adolescent; Antiretroviral Therapy; Highly Active; Adherence; Viral Load; CD4 Lymphocyte Count
Mortality among patients with tuberculosis (TB)/HIV is highest during the first few months of antituberculous therapy. The objective of this study was to assess the factors associated with early mortality among TB/HIV patients and whether these factors are similar for HAART naïve and those with prior HAART initiation.
Prospective cohort study including HIV patients with tuberculosis confirmed by culture, cared for at a referral center in Rio de Janeiro, Brazil. Multivariable Cox analysis was used to assess predictors of mortality within 3 months of antituberculous therapy.
Among 227 patients included, 90 (40%) started HAART before TB diagnosis. The median time to TB diagnosis after ARV initiation was 5.9 months (interquartile range [IQR] 3.0–8.9 months). Fourteen patients (6%) died within the first 3 months. Mortality was not different between patients previously started on HAART and those who were naïve to it. In the overall adjusted analysis, HAART use during TB treatment (hazard ratio [HR] = 0.21, 95% confidential interval [CI] = 0.06–0.72) and CD4 lymphocyte count >100 cells/mm3 (HR = 0.21, 95% CI = 0.04–0.99) were associated with lower mortality, while subjects with unknown baseline CD4 lymphocyte count (HR = 9.39, 95% CI = 2.56–34.5) had higher mortality. In subgroup analysis, among HAART naïve subjects, disseminated TB (HR = 5.32, 95% CI = 1.09–25.8) and unknown baseline CD4 lymphocyte count (HR = 13.2, 95% CI = 2.71–64.5) were associated with significantly higher mortality, while HAART (HR = 0.14, 95% CI = 0.03–0.69) predicted a better outcome. Among subjects previously started on HAART, mortality was significantly associated with duration of TB symptoms >120 days (HR = 6.15, 95% CI = 1.15–32.9).
Predictors of early mortality among TB/HIV patients may vary according to the timing of HAART initiation. Among HAART naïve patients, mortality was influenced by baseline clinical severity, HAART use and, possibly, the quality of care preceding TB diagnosis. For patients with prior HAART initiation, longer delays in TB diagnosis predicted a significantly higher mortality.
In 1997, Taiwan made highly active antiretroviral therapy (HAART) available without cost to HIV-infected persons; in 2001, a national web-based surveillance system was implemented. Healthcare workers use the system to monitor patients' conditions and can intervene when necessary. Free HAART, coupled with the surveillance system, appears to have increased survival rates of HIV-infected persons with tuberculosis in Taiwan.
HIV/TB coinfection; HAART; surveillance system; mortality; influenza A (H5N1); AZT
Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California.
The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode.
Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p = 0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p = 0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p = 0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p = 0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p = 0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p = 0.0171).
The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions.
We characterized patterns of highly active antiretroviral therapy (HAART) use and predictors of non-structured treatment interruptions (NTIs) among injection drug users (IDUs) in Baltimore, MD.
335 IDUs who initiated HAART from 1996-2006 were studied. NTIs were defined as any subsequent six-month interval where HAART was not reported. Predictors of the first NTI and subsequent restart of HAART were examined using Cox regression.
260 (78%) reported ≥1 NTI. Of 215 with ≥1 follow-up visit after the NTI, 44 (20%) never restarted HAART, 62 (29%) restarted and remained on HAART and 109 (51%) reported multiple NTIs. NTIs were less likely among those who initiated HAART in later calendar years and hada recent outpatient visit and more likely among women, persons with detectable HIV RNA at the prior visit and those who reported injecting daily. Among those with NTIs, interuptions occurred earlier in persons who were younger, did not have a prior AIDS diagnosis and were actively injecting; NTIs lasted longer in persons who had higher HIV RNA levels, were incarcerated and drinking alcohol. A recent outpatient visit and not actively injecting were associated with restarting HAART.
NTIs were common in this population and occurred most frequently in the setting of active drug use and disruption of health care. Effective linkages between primary care for HIV and substance abuse treatment may improve HAART outcomes in this population.
Highly active antiretroviral therapy; injection drug users; treatment interruptions
In sub-Saharan Africa, human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. Sub-Saharan Africa has seen the woeful failure of World Health Organization (WHO) targets of detecting 70% of the infectious cases of tuberculosis and curing > or =85%. Current treatment of Mycobacterium tuberculosis in most resource limited settings is comprised of a four-drug initial antituberculosis regimen for two months, followed by either a two-drug continuation phase of antituberculosis regimen for four months or six months depending on the medications. Many countries in sub-Saharan Africa are scaling up with highly active antiretroviral therapy (HAART), using one of the first-line regimens that consist of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our current HAART regimen and antituberculosis drugs continue to give us a therapeutic challenge in terms of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndromes. Scientific research is needed in the areas of diagnosis, treatment and prevention of tuberculosis in sub-Saharan Africa. Such research could be facilitated due to greater availability of funding than a decade ago.
The profile of immune activation markers in tuberculosis and HIV-infected patients is already known. The impact of simultaneous infections on the immune parameters is still not fully explored.
We conducted a prospective study to estimate trajectories of activated T cell subsets and the profile of anti- and pro-inflammatory cytokines in a group of HIV-TB individuals, previously naïve for HAART, recruited from a randomized clinical trial during TB treatment and first antiretroviral therapy with efavirenz. Patients were evaluated according to the immunosuppression levels at baseline as group 1 (CD4<200 cells/mm3) and group 2 (CD4>200 cells/mm3). These parameters were measured at the time of HAART initiation (started about 30 days after the onset of TB treatment) and at the follow-up visits after 30, 60, 90 and 180 days. Trajectories were estimated using least squares estimates of the coefficients of a restricted cubic spline function in time after adjusting for subject effects, bootstrapping it 500 times.
Increase of CD4 T cell counts and suppression of HIV viral load were observed for all patients under HAART and TB treatment. Descendent trajectories were observed for the activated CD8+/CD38+ and CD3+/HLA-DR+ T cell subsets, and for plasma concentration of gamma- interferon (IFN-γ). Except for TNF-α and IL-2 discrete variations were observed for the other cytokines. Differences in the trajectories of these parameters were observed for groups 1 and 2. Higher values of IFN-γ, IL-2, IL-6 and IL-10 were observed for group 1 from the baseline to two months after treatment initiation, whereas reduced levels of TNF-α were observed for this group between 60 and 120 days of HAART.
Independent of the immunosuppression profile at baseline, HIV-TB patients under HAART were able to recover the CD4+ T cell counts, and control viral replication and immune activation parameters over time.
To understand the epidemiology of tuberculosis (TB) and HIV co-infection in California, we cross-matched incident TB cases reported to state surveillance systems during 1993–2008 with cases in the state HIV/AIDS registry. Of 57,527 TB case-patients, 3,904 (7%) had known HIV infection. TB rates for persons with HIV declined from 437 to 126 cases/100,000 persons during 1993–2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co-infected with TB–HIV during 2001–2008 were significantly more likely than those infected before highly active antiretroviral therapy became available to be foreign born, Hispanic, or Asian/Pacific Islander and to have pyrazinamide-monoresistant TB. Death rates decreased after highly active antiretroviral therapy became available but remained twice that for TB patients without HIV infection and higher for women. In California, HIV-associated TB has concentrated among persons from low and middle income countries who often acquire HIV infection in the peri-immigration period.
Tuberculosis; HIV; TB–HIV co-morbidity; HAART; California; Mycobacterium tuberculosis and other mycobacterial diseases; United States; co-infection; USA; highly active antiretroviral therapy
Risk of pneumocystosis after discontinuation of primary or secondary prophylaxis among HIV-infected patients before CD4 counts increase to ≧200 cells/μL (early discontinuation) after receiving highly active antiretroviral therapy (HAART) is rarely investigated.
Medical records of 660 HIV-infected patients with baseline CD4 counts <200 cells/μL who sought HIV care and received HAART at a university hospital in Taiwan between 1 April, 1997 and 30 September, 2007 were reviewed to assess the incidence rate of pneumocystosis after discontinuation of prophylaxis for pneumocystosis.
The incidence rate of pneumocystosis after HAART was 2.81 per 100 person-years among 521 patients who did not initiate prophylaxis or had early discontinuation of prophylaxis, which was significantly higher than the incidence rate of 0.45 per 100 person-years among 139 patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL (adjusted risk ratio, 5.32; 95% confidence interval, 1.18, 23.94). Among the 215 patients who had early discontinuation of prophylaxis after achievement of undetectable plasma HIV RNA load, the incidence rate of pneumocystosis was reduced to 0.31 per 100 person-years, which was similar to that of the patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL (adjusted risk ratio, 0.63; 95% confidence interval, 0.03, 14.89).
Compared with the risk of pneumocystosis among patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL after HAART, the risk was significantly higher among patients who discontinued prophylaxis when CD4 counts remained <200 cells/μL, while the risk could be reduced among patients who achieved undetectable plasma HIV RNA load after HAART.