Timing Of Highly Active Antiretroviral Therapy Initiation Research Articles

Impaired Hematological Status Increases the Risk of Mortality among HIV-Infected Adults Initiating Antiretroviral Therapy in Tanzania

Hematological status may predict HIV disease progression and mortality among adults initiating highly active antiretroviral therapy (HAART). We aimed to examine the relation of anemia and iron status at HAART initiation with survival and morbidity outcomes. We conducted a case-cohort study of 570 HIV-infected adults initiating HAART who were enrolled in a trial of multivitamins in Tanzania. Hemoglobin, serum ferritin, and hepcidin concentrations were assessed at HAART initiation and participants were followed up monthly. We adjusted serum ferritin for inflammation using a regression correction method to characterize hematological status. Cox proportional hazards models were used to estimate HRs for mortality and incident clinical outcomes. We found an 83% prevalence of anemia, 15% prevalence of iron deficiency anemia, and 66% prevalence of anemia of chronic diseases (ACD). The prevalence of elevated iron was 33% and 19% had iron deficiency (ID). After multivariate adjustment, severe anemia (HR: 2.57; 95% CI: 1.49, 4.45) and ACD (HR: 4.71; 95% CI: 2.91, 7.62) were associated with increased risk of mortality as compared with nonanemic participants. In addition, both ID (HR: 2.65; 95% CI: 1.08, 7.78) and elevated iron (HR: 2.83; 95% CI: 2.10, 3.82) were associated with increased risk of mortality as compared with normal iron concentrations. Severe anemia and elevated iron concentrations were associated with incident wasting and >10% weight loss (P values<0.05). Anemia and both ID and elevated iron were associated with increased mortality among HIV-infected adults initiating HAART. Safety and efficacy studies including anemia etiology, timing of HAART initiation, and dose of iron supplementation among HIV patients appear warranted.This trial was registered at clinicaltrials.gov as NCT00383669.

Relationship between Body Mass Index and Mortality in HIV-Infected HAART Users in the Women's Interagency HIV Study.

BackgroundEarly HIV studies suggested protective associations of overweight against mortality, yet data are lacking for the era of potent highly active antiretroviral therapy (HAART). We evaluated associations of pre-HAART initiation body mass index (BMI) with mortality among HAART-using women.MethodsProspective study of time to death after HAART initiation among continuous HAART users in the Women’s Interagency HIV Study. Unadjusted Kaplan–Meier and adjusted proportional hazards survival models assessed time to AIDS and non-AIDS death by last measured pre-HAART BMI.ResultsOf 1428 continuous HAART users 39 (2.7%) were underweight, 521 (36.5%) normal weight, 441 (30.9%) overweight, and 427 (29.9%) obese at time of HAART initiation. A total of 322 deaths occurred during median follow-up of 10.4 years (IQR 5.9–14.6). Censoring at non-AIDS death, the highest rate of AIDS death was observed among underweight women (p = 0.0003 for all 4 categories). In multivariate models, women underweight prior to HAART died from AIDS more than twice as rapidly vs. normal weight women (aHR 2.04, 95% CI 1.03, 4.04); but being overweight or obese (vs. normal weight) was not independently associated with AIDS death. Cumulative incidence of non-AIDS death was similar across all pre-HAART BMI categories.ConclusionsAmong continuous HAART-using women, being overweight prior to initiation was not associated with lower risk of AIDS or non-AIDS death. Being underweight prior to HAART was associated with over double the rate of AIDS death in adjusted analyses. Although overweight and obesity may be associated with many adverse health conditions, neither was predictive of mortality among the HAART-using women.

Severe pneumonia in HIV-infected and exposed infants in a paediatric ICU

Background. Pneumocystis jiroveci pneumonia is still a common cause of severe disease in HIV-infected infants <5 months of age. Despite attention to the prevention of mother-to-child transmission programme in South Africa (SA), HIV testing remains incomplete and infants are still at risk. The management of Pneumocystis pneumonia requires ventilation strategies and combination antibiotics. Methods. A prospective but open intervention was performed on all HIV-exposed patients admitted with severe pneumonia to the paediatric intensive care unit (PICU) at Steve Biko Academic Hospital, SA, during a 3-year period from January 2009 to December 2011. All patients were treated with ampicillin, amikacin, co-trimoxazole, prednisone and intravenous gancilovir. Highly active antiretroviral therapy (HAART) was initiated in the PICU as soon as tuberculosis was excluded and HIV status confirmed with an HIV viral load (VL). Routine blood and tracheal specimens were cultured for bacteria and tested by direct fluorescent antigen testing for P. jiroveci . Cytomegalovirus (CMV) VL was tested. All infants were ventilated in a standard fashion and none were oscillated. Results. A total of 87 patients were admitted during the 3-year period. Of these, 29 patients were excluded from the study because they were HIV-unexposed. Ten patients died during the 3-year period. In a multivariate analysis of the presence or absence of P. jiroveci , HIV VL, CD4 count, timing of HAART initiation and CMV VL, no single factor was documented to influence mortality. Conclusion. Mortality from Pneumocystis pneumonia continues to decrease in this PICU. No single factor is responsible and yet all therapeutic strategies contribute to survival. A national policy and guideline is urgently required.

Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study.

A high delivery maternal plasma HIV-1 RNA level (viral load [VL]) is a risk factor for mother-to-child transmission and poor maternal health. To identify factors associated with detectable VL at delivery despite initiation of highly active antiretroviral therapy (HAART) during pregnancy. Multicenter observational study. (ClinicalTrial.gov: NCT00028145). 67 U.S. AIDS clinical research sites. Pregnant women with HIV who initiated HAART during pregnancy. Descriptive summaries and associations among sociodemographic, HIV disease, and treatment characteristics; pregnancy-related risk factors; and detectable VL (>400 copies/mL) at delivery. Between 2002 and 2011, 671 women met inclusion criteria and 13.1% had detectable VL at delivery. Factors associated with detectable VL included multiparity (16.4% vs. 8.0% nulliparity; P=0.002), black ethnicity (17.6% vs. 6.6% Hispanic and 6.6% white; P<0.001), 11th grade education or less (17.6% vs. 12.1% had a high school diploma; P=0.013), initiation of HAART in the third trimester (23.9% vs. 12.3% and 8.6% in the second and trimesters, respectively; P=0.003), having an HIV diagnosis before the current pregnancy (16.1% vs. 11.0% during the current pregnancy; P=0.051), and having the first prenatal visit in the third trimester (33.3% vs. 14.3% and 10.5% in the second and third trimesters, respectively; P=0.002). Women who had treatment interruptions or reported poor medication adherence were more likely to have detectable VL at delivery. Data on many covariates were incomplete because women entered the study at varying times during pregnancy. A total of 13.1% of women who initiated HAART during pregnancy had detectable VL at delivery. The timing of HAART initiation and prenatal care, along with medication adherence during pregnancy, were associated with detectable VL at delivery. Social factors, including ethnicity and education, may help identify women who could benefit from focused efforts to promote early HAART initiation and adherence. U.S. Department of Health and Human Services.

Predicting mortality in HIV-infected children initiating highly active antiretroviral therapy in a resource-deprived setting.

While highly active antiretroviral therapy (HAART) programs have been scaled up across sub-Saharan Africa, no prognostic models for the prediction of mortality risk for children initiating HAART are widely available. Current clinical prediction tools for human immunodeficiency virus (HIV)-infected children are derived from pre-HAART data and therefore cannot predict mortality for children initiating HAART. The purpose of this study was to develop a mortality risk scoring system for HIV-infected children beginning HAART in a resource-deprived setting. Observational data from HIV-infected children initiating HAART from December 2004 through March 2012 in Kinshasa, Democratic Republic of Congo, were analyzed. Cox proportional hazards models were constructed to assess associations between demographic and clinical characteristics at the time of HAART initiation and mortality. Each child received a model-based risk score predicting mortality after HAART initiation. By 31 March 2012, 1010 children had started HAART. One hundred three children (10.2%) died at a median of 5.3 months post-HAART initiation, yielding a mortality rate of 3.4 deaths per 100 child-years. The final mortality prediction model included undernutrition, low CD4 count, HIV symptoms, and low total lymphocyte count. These factors were highly predictive of mortality in the study population (C statistic = 0.79) and performed well when applied to the validation population (C statistic = 0.77). Mortality among children starting HAART in resource-deprived settings can be predicted using a simple scoring system incorporating several readily available factors. Identifying predictors of mortality will help clinicians target modifiable risk factors, such as undernutrition, which are not directly addressed by HAART.

Effect of CD4+ T-lymphocyte count on hospital outcome of elective general thoracic surgery patients with human immunodeficiency virus

Traditionally, the chief surgical indicator for human immunodeficiency virus (HIV)-infected patients was the CD4-positive T-lymphocyte count; however, there is no current consensus. Reports published after 2006 indicated that HIV-infected patients had a higher incidence of postoperative pneumonia and higher 12-month mortality rates. In addition, CD4 counts had no relation to the in-hospital outcome. Therefore, we retrospectively examined all of the previous patients who underwent operations in our department on the basis of these findings. Regardless of the initiation of highly active anti-retroviral therapy (HAART), we retrospectively reviewed 10 general thoracic surgeries performed in our department according to the CD4 cell count, HIV-ribonucleic acid (RNA) viral load, time of HAART initiation, operating time, amount of blood, postoperative course, and period of observation. There was no incidence of postoperative pneumonia or wound infection. There were also no complications during the perioperative period. One patient died 7 months after surgery. Our retrospective study demonstrates that the indicator for elective general thoracic surgery is not the CD4-positive T-lymphocyte count and that the initiation of HAART may reduce the 12-month mortality rates. In HIV-positive patients, regardless of the CD4-positive T-lymphocyte count, surgeons can operate in the same manner as they would with HIV-negative patients.

Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters.

To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL. In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs). Of 9455 patients with 52,268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively. Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.

Comparison of HIV-Infected Patients' Characteristics and Clinical Outcomes Between Cohort-Dependent and Independent Patients: Korean HIV Cohort Study

Comparison of HIV-Infected Patients' Characteristics and Clinical Outcomes Between Cohort-Dependent and Independent Patients: Korean HIV Cohort Study

Smear positive pulmonary tuberculosis among HIV patients receiving Highly Active Antiretroviral Therapy in Dar es Salaam, Tanzania

Globally, tuberculosis-HIV co-infections are on the increase. In 2007, 15% (1.37 million) of the tuberculosis cases were HIV-positive tuberculosis (TB). This cross-sectional study was conducted in February 2009 to assess the effect of the level of CD4 lymphocyte counts on the development of smear positive pulmonary TB (PTB) among HIV patients before and after initiation of highly active antiretroviral therapy (HAART). A total of 155 HIV patients who were on HAART programme were enrolled and out of these 42 (27.1%) were smear positive PTB. Of the 42 PTB patients, 38 (90.5%) were also infected with HIV and were already at initiation of HAART. There was no association between the development of smear positive PTB and socio-demographic characteristics among HIV patients before and after HAART initiation (P>0.05). A larger proportion of HIV+PTB patients diagnosed before and after HAART initiation was found with CD4 lymphocyte count <200cells/microl. However, the difference was not statistically significant (P =0.092). Among HIV patients who were diagnosed to be smear positive PTB after HAART initiation, their CD4 lymphocyte counts at time of TB diagnosis was lower than their CD4 lymphocyte counts at time of HAART initiation. The four patients diagnosed with PTB after HAART initiation had mean CD4 lymphocyte counts at HAART initiation not statistically different from that at TB diagnosis (t=0.715, P=0.526). The median time period within which the diagnosis of smear positive PTB was made after HAART initiation was 22 weeks and the mean time was 66.75 weeks. These findings provide evidence that development of smear positive PTB after HAART initiation may occur at any level of CD4 lymphocyte count (P<0.05). This study was limited by the relatively small sample size, we therefore recommend more studies involving a larger sample size in order to estimate more accurately the effect of both level of CD4 lymphocyte count and HAART on the development of smear positive PTB among HIV patients on treatment.

Initiation of Antiretroviral Treatment in Women After Delivery Can Induce Multiclass Drug Resistance in Breastfeeding HIV-Infected Infants

The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003). Postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.

The Impact of Kidney Function at Highly Active Antiretroviral Therapy Initiation on Mortality in HIV-Infected Women

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 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. 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. Chronic kidney disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history, and CD4 cell count (hazard ratio 2.23, 95% confidence interval: 1.45-3.43). Adjustment for hypertension and diabetes history attenuated this association (hazard ratio = 1.89, confidence interval: 0.94-3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (hazard ratio = 1.09, confidence interval: 1.00-1.19, per 20% decrease in estimated glomerular filtration rate). 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 chronic kidney disease in HIV-infected persons.

Preterm delivery in HIV positive women taking highly active antiretroviral therapy

BackgroundFor women with HIV in resource-rich countries antenatal practice has shifted away from use of zidovudine monotherapy towards routine use of highly active antiretroviral therapy (HAART), in order to suppress...

Cryptococcal Immune Reconstitution Inflammatory Syndrome after Antiretroviral Therapy in AIDS Patients with Cryptococcal Meningitis: A Prospective Multicenter Study

A prospective multicenter study of cryptococcal immune reconstitution inflammatory syndrome (IRIS) was conducted as a substudy of the Bacteriology and Mycology Study Group 3-01. Of 101 AIDS patients with cryptococcal meningitis who received highly active antiretroviral therapy (HAART), 13 experienced cryptococcal IRIS. No association between the timing of HAART initiation and the diagnosis of IRIS was identified. Increased baseline serum cryptococcal antigen (CrAg) titer was a risk factor for cryptococcal IRIS.

Are the effects of isoniazid preventive therapy and highly active antiretroviral therapy additive in preventing HIV-associated tuberculosis?

Golub et al. recently reported a retrospective analysis of rates of incident tuberculosis (TB) in a large observational cohort of 2778 patients accessing HIV care in rural and urban South Africa [1]. The TB incidence rate was highest (7.1/100 person-years; 95%CI 6.2–8.2) during the period of care when patients did not receive isoniazid preventive therapy (IPT) or highly active antiretroviral therapy (HAART). The rates were lower during person-time that accrued during follow-up after initiation of IPT (5.2/100 PYs; 95%CI 3.4–7.8) and during follow-up on HAART alone (4.6/100PYs, 95%CI 3.4–6.2). The rate was lower still (1.1/100 PYs 95%CI 0.2–7.6) during person-time accrued during sequential IPT and HAART (IPT+HAART). The authors concluded that TB risk was significantly reduced by IPT in HAART-treated adults. It was further concluded that “the dramatic reduction in TB risk” demonstrated in this study together with supportive data from a similarly analysed study from Brazil [2] indicate that widespread use of IPT should be implemented in conjunction with the roll-out of HAART. Firstly, it is notable that HAART alone but not IPT alone was associated with significantly lower TB incidence rates compared to the non-intervention group in both adjusted and unadjusted analyses. In addition, no significant difference was observed in the incidence rates comparing the HAART only and the IPT+HAART groups. Thus, these analyses do not demonstrate a significant additive effect in TB prevention by treating patients with both IPT and HAART. In further analysis, Kaplan-Meier survival estimates appeared to support a significant difference between TB-free survival in the IPT+HAART group and all other treatment groups. Surprisingly, however, the Kaplan-Meier analysis showed that no TB events occurred among patients in the IPT+HAART group during the first 3 years of observation despite low CD4 cell counts (median, 176 cells/μL at the time of HAART initiation). We are concerned that these conclusions may have been erroneously drawn as a result of analysis of groups with significant selection bias. Among 62 patients within the IPT+HAART group, 61 had initiated IPT a median of 1.0 years (IQR 0.5–1.9) before starting HAART. In this analysis, person-time of observation was censored when patients developed TB. Thus, only selected patients who remained alive and free of TB during the period between IPT initiation and HAART initiation would be eligible for inclusion in the IPT+HAART group. Thus, the TB incidence rate during the median of 1.0 years (IQR 0.5–1.9) of observation before HAART would have been inappropriately assessed as zero cases/100 PYs. However, the IPT-HAART group had markedly lower CD4 cell counts than the IPT alone group and therefore the true incidence rate would very likely have exceeded 5.2 cases/100 PYs in the pre-ART period, potentially adding several more cases to the single case reported in this treatment group. Furthermore, no deaths were reported in this survival analysis and additional cases of TB may have remained unascertained among those who died. Inclusion of such additional TB cases would likely have negated the apparent observed group differences in the Kaplan-Meier analysis. The benefits of IPT in HIV-infected patients included in randomised controlled trials have been clearly demonstrated [3,4]. However, the lack of significant effectiveness of IPT alone in this South African study and in the large Brazilian cohort study [2] raises concerns about the effectiveness of this intervention in routine clinical practice. Potential explanations for lack of IPT efficacy may include poor adherence and the inclusion of TST-negative individuals. However, in both these studies the strongest predictor of TB incidence rates was the baseline CD4 cell count, with 60-90% lower rates in those with CD4 cell strata above 200 cells/uL. Furthermore, there are no data from randomised controlled trials that specifically demonstrate the efficacy of primary IPT at low CD4 cell counts. We wonder therefore whether the inclusion of significant numbers of individuals with CD4 cell counts under 200 cells/uL may partially explain the apparent lack of statistically significant reduction of TB rates during and after IPT. In view of the clear benefits of HAART on survival and TB incidence [5], it would be unethical to perform studies of 6 months IPT or placebo before initiating HAART in eligible patients. TB rates during early HAART are very high and are related to the baseline CD4 cell count at treatment initiation, remain high in those with sub-optimal CD4 cell recovery and continue to be elevated even in those with optimal CD4 cell recovery [7,8,9]. There remains an urgent need to demonstrate an additive benefit of IPT over and above CD4 cell recovery after initiation of HAART and to identify the optimal timing of IPT before this can be scientifically justified as an integrated component of HAART roll-out.

Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

HIV-1 infection induces a progressive disruption of the B cell compartment impairing long-term immune responses to routine immunizations. Depletion of specific memory B cell pools occurs during the 1st stages of the infection and cannot be reestablished by antiretroviral treatment. We reasoned that an early control of viral replication through treatment could preserve the normal development of the memory B cell compartment and responses to routine childhood vaccines. Accordingly, we evaluated the effects of different highly-active antiretroviral therapy (HAART) schedules in 70 HIV-1 vertically-infected pediatric subjects by B cell phenotypic analyses, antigen-specific B cell enzyme-linked immunosorbent spot (ELISpot) and ELISA for common vaccination and HIV-1 antigens. Initiation of HAART within the 1st year of life permits the normal development and maintenance of the memory B cell compartment. On the contrary, memory B cells from patients treated later in time are remarkably reduced and their function is compromised regardless of viral control. A cause for concern is that both late-treated HIV-1 controllers and noncontrollers loose protective antibody titers against common vaccination antigens. Timing of HAART initiation is the major factor predicting the longevity of B cell responses in vaccinated HIV-1-infected children.

HIV infection in the elderly

The prevalence of HIV in patients over the age of 50 years is increasing. Although older patients may achieve equal or better virologic suppression at equal rates compared with younger patients, the immunologic benefit of highly active antiretroviral therapy (HAART) in older patients may be reduced compared with younger patients. Comorbidities are more common in older patients than younger patients and can impact management of HIV in these patients. Providers must be cognizant of drug-drug interactions and side effects of HAART regimens when selecting an antiretroviral regimen in older HIV patients. As the HIV-infected population ages, there is a growing need to better determine the ideal HAART regimen and timing of HAART initiation in older patients.

Haematological changes after switching from stavudine to zidovudine in HIV-infected children receiving highly active antiretroviral therapy

In resource-limited countries, stavudine (d4T) is commonly used as part of the initial highly active antiretroviral therapy (HAART) regimen. Many patients who subsequently develop lipodystrophy switch from d4T to zidovudine (ZDV), a drug that can be myelotoxic. We aimed to study the spectrum and severity of haematological changes following this substitution. This was a retrospective cohort study. The inclusion criteria were as follows: HIV-infected children were included who (1) were 2-15 years old at the time of HAART initiation, (2) had not been diagnosed as having haematological diseases, (3) had been receiving a first HAART regimen consisting of either nevirapine or efavirenz, together with lamivudine and d4T, for at least 48 weeks and (4) had switched from d4T to ZDV at least 48 weeks previously. Seventy-eight children were included in the study. Thirty-six (46%) were male. The mean age was 10.3 years (standard deviation 3.1 years). The switch had been made a median time of 65 weeks (range 48-97 weeks) previously. There was no significant change in CD4 lymphocyte count or percentage, or HIV RNA level, after the switch. There was a statistically significant decrease in haemoglobin level (12.6 vs.12.1 g/dL; P<0.001), total white blood cell (WBC) count (8088 vs. 6910 cells/microL; P<0.001) and absolute neutrophil count (ANC) (4320 vs. 3448 cells/microL; P<0.001). However, the decreases never reached Division of AIDS grade 3 or 4 severity, and none of the patients had clinical symptoms or signs of anaemia, leukopenia, or neutropenia. No participant had to discontinue ZDV during the 48-week follow-up period. In a paediatric population, statistically significant decreases in haemoglobin level, WBC count and ANC occurred following the substitution of d4T with ZDV, but the magnitudes of the decreases were small and not clinically significant.

Tuberculosis and HIV Co-Infection

HIV and tuberculosis (TB) are leading global causes of mortality and morbidity, and yet effective treatment exists for both conditions. Rifamycin-based antituberculosis therapy can cure HIV-related TB and, where available, the introduction of highly active antiretroviral therapy (HAART) has markedly reduced the incidence of AIDS and death. Optimal treatment regimens for HIV/TB co-infection are not yet clearly defined. Combinations are limited by alterations in the activity of the hepatic cytochrome P450 (CYP) enzyme system, which in particular may produce subtherapeutic plasma concentrations of antiretroviral drugs. For example, protease inhibitors often must be avoided if the potent CYP inducer rifampicin is co-administered. However, an alternative rifamycin, rifabutin, which has similar efficacy to rifampicin, can be used with appropriate dose reduction. Available clinical data suggest that, for the majority of individuals, rifampicin-based regimens can be successfully combined with the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Most available HAART regimens in areas that have a high burden of TB contain one or the other of these drugs as a backbone. However, significant questions remain as to the optimal dose of either agent required to ensure therapeutic plasma concentrations, especially in relation to particular ethnic groups. The timing of HAART initiation after starting antituberculosis therapy continues to be controversial. Debate centres upon whether early initiation of HAART increases the risk of paradoxical reactions (immune reconstitution-related events) and other adverse events, or whether delay greatly elevates the risk of disease progression. Further prospective clinical data are needed to help inform practice in this area.

Change in T-Lymphocyte Count after Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients with History of Mycobacterium Avium Complex Infection

Objective To compare changes in CD4+, CD8+ and total lymphocyte counts after initiation of highly active anti-retroviral therapy (HAART) between HIV-infected patients with and without a recent history of Mycobacterium avium complex (MAC) infection. Method Matched exposed-non-exposed retrospective cohort study. Results Fifty-one patients with a recent history of MAC infection (MAC+) started a combination of at least three antiretroviral drugs. They were individually matched to 145 patients without any history of MAC infection (MAC-) according to CD4+ T-cell count (±30 cells/mm3), previous experience of antiretroviral treatment, AIDS clinical stage at the time of HAART initiation (baseline), age (±10 years) and gender. MAC+ and MAC- patients presented comparable median levels of total lymphocytes (488 vs 688/mm3, P=0.09), CD4+ (11 vs 16/mm3, P=0.15), CD8+ count (359 vs 386/mm3, P=0.39) and plasma HIV RNA (5.3 vs 5.1 log10 copies/ml, P=0.22) at baseline. After 6 months on HAART, the median increase of CD4+ T-cell count was 28 cells/mm3 (interquartile range [IQR]: 1–63) in MAC+ and 72 cells/mm3 (IQR: 34–120) in MAC- patients ( P&lt;0.0001), whereas the percentage of CD4+ T cells was not significantly different between the two groups ( P=0.13). Comparable differences were observed for total lymphocytes and CD8+ T cells ( P&lt;0.001). The 6 months decline of plasma HIV RNA was not significantly different according to MAC exposure (-1.6 in MAC+ vs -1.8 log10 copies/ml in MAC- patients, P=0.65). Results were confirmed after adjustment for other characteristics than the matching variables and after taking into account potential informative bias due to unbalanced number of deaths between the two groups. Conclusion MAC infection at the time of HAART initiation is an important deleterious factor for immune reconstitution. A better understanding of the underlying mechanism and an evaluation of additional treatment strategies are necessary to help immune restoration in such circumstances.

Update on the Virologic and Immunologic Response to Highly Active Antiretroviral Therapy.

Highly active antiretroviral therapy (HAART) delays clinical progression by suppressing viral replication, measured by a substantial reduction in HIV RNA, allowing the immune system to reconstitute, measured in most studies by an increase in CD4 cells. These virologic and immunologic consequences do not occur uniformly among HAART users. Markers of HIV disease stage at the time of HAART initiation are critical determinants of the progression while receiving HAART. In this report, we review studies describing the heterogeneous virologic and immunologic progression after the initiation of HAART, discuss methodologic concerns in the study of the response of biomarkers, and update findings obtained in the Multicenter AIDS Cohort Study, which show that CD4 cell count, history of antiretroviral therapy, and age at the time of initiation are independent determinants of response.