HIV antiretroviral treatment: early versus later

OBJECTIVES: Cohort studies indicate that starting highly active antiretroviral therapy (HAART) when the CD4+ T-cell count is less than 200 cells/muL is associated with poor outcomes. These studies have been unable to address how early HAART should be initiated, however. This report uses a modeling approach to compare starting HAART at a mean CD4+ T-cell count greater than 350 cells/microL (early) versus less than 350 cells/microL but greater than 200 cells/microL (later). METHODS: A Markov model tracks people with HIV infection through 6 disease stages defined by CD4+ T-cell count ranges over a 25-year period. Transition probabilities between the disease stages for 6-month periods vary according to initial viral load. Sequences of different first-line, second-line, and "salvage" antiretroviral regimens are defined, and their impact on transition probabilities is estimated. HAART effectiveness is based on data from an urban hospital-based HIV clinic, supplemented by clinical trial data. The model computes the incremental cost-effectiveness of alternative treatment patterns and includes sensitivity analyses for a range of plausible alternative input values. RESULTS: Starting HAART earlier rather than later increases total lifetime costs by $19,074, increases years of life by 1.21 years, increases discounted quality-adjusted life-years by 0.61, and has an incremental cost-effectiveness ratio of $31,266 per quality-adjusted life-year. Early therapy is more cost-effective when the impact of HAART on well-being is smaller. CONCLUSIONS: Initiation of HAART at a CD4+ T-cell count greater than 350 cells/microL may be cost-effective (less than $50,000 per quality-adjusted life-year) compared with initiating HAART at a CD4+ T-cell count less than 350 cells/microL but greater than 200 cells/muL and may result in longer quality-adjusted survival.     

Thymic volume predicts CD4 T-cell decline in HIV-infected adults under prolonged treatment interruption

OBJECTIVE: To analyze the predictive capacity of thymic volume in CD4 T-cell loss after treatment interruption in HIV-infected patients with high nadir CD4 count. METHODS: Thirty-nine HIV-infected patients with CD4 counts greater than or equal to 500 cells/microL, nadir CD4 counts greater than or equal to 250 cells/microL, and plasma viral loads less than 50 copies/mL for at least the past 12 months began a treatment interruption program. The event of interest for this study was the decrease of CD4 count below 350 cells/microL. Kaplan-Meier curves were used for all time-to-event analyses, and log-rank tests were used for comparison between groups in the univariate analysis. All variables with statistical association with CD4 T-cell loss were analyzed using multivariate Cox proportional hazards regression models. RESULTS: Twenty-three percent of the patients had a decrease in CD4 count to less than 350 cells/microL. In the univariate analysis, only thymic volume was statistically significant with this event (P = 0.02). Nadir CD4 count nearly reached statistical significance. However, age, sex, HCV coinfection, CD4 count, T-cell receptor excision circle-bearing cells, and early viral load rebound did not show statistical differences. Thymic volume and CD4 T-cell loss were independently associated using Cox proportional hazards regression model (P = 0.04; relative risk, 0.76; 95% confidence interval, 0.59-0.99). CONCLUSIONS: In this study, we demonstrate for the first time that thymic volume predicts CD4 T-cell loss in patients with nadir CD4 count greater than or equal to 250 cells/muL under treatment interruption.     

Short-term CD4 cell response after highly active antiretroviral therapy initiated at different times from seroconversion in 1,500 seroconverters

The effect of HIV infection duration and CD4 cell count on short-term CD4 response was evaluated in treatment-naive seroconverters using logistic regression adjusted for CD4 count before highly active antiretroviral therapy (HAART) as well as for exposure category, age, sex, acute infection, and cohort. This association was also investigated in pretreated seroconverters, further adjusting for prior therapy. CD4 response (increase of >100 cells/microL at 6 months) was more likely if HAART was initiated in the first year following seroconversion (OR = 1.50 [95% CI: 1.07-2.10] compared with 2-5 years). There was no improvement in response from initiating HAART with CD4 count >350 cells/microL compared with 201 to 350 cells/microL. Below 200 cells/microL, however, the chance of a CD4 response appeared to be reduced (OR = 0.72 [95% CI: 0.40-1.28] for 0-200 cells/microL compared with 201-350 cells/microL, P = 0.26). Results were similar for pretreated individuals. Further, in pretreated individuals, a CD4 response was less likely if the CD4 nadir was lower than the pre-HAART CD4 count (OR = 0.18 [95% CI: 0.10-0.36] for >150 cells/microL difference between nadir and pre-HAART CD4 count vs. no difference, P < 0.001). Given the limitations of observational studies, particularly the inability to control for unmeasured confounders, these findings suggest that the initiation of HAART within the first year following seroconversion appears to improve short-term immunologic response. After that time, there is little to be gained in terms of short-term response from initiating HAART before reaching a CD4 count of 200 cells/microL.     

The impact of adherence on CD4 cell count responses among HIV-infected patients

BACKGROUND: There have been concerns that irreversible immune damage may result if highly active antiretroviral therapy (HAART) is initiated after the CD4 cell count declines to below 350 cells/microL; however, the role of antiretroviral adherence on CD4 cell count responses has not been well evaluated. METHODS: We evaluated CD4 cell count responses of 1522 antiretroviral-naive patients initiating HAART who were stratified by baseline CD4 cell count (<50, 50-199, and >or=200 cells/microL) and adherence. RESULTS: Among patients starting HAART with <50 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 200 cells/microL (interquartile range [IQR]: 130-290) for adherent patients versus 60 cells/microL (IQR: 10-130) for nonadherent patients. Similarly, among patients starting HAART with 50 to 199 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 300 cells/microL (IQR: 180-390) versus 125 cells/microL (IQR: 40-210) for nonadherent patients. In Cox regression analyses, adherence was the strongest independent predictor of the time to a gain of >or=50 cells/microL from baseline (relative hazard [RH] = 2.88, 95% confidence interval [CI]: 2.46-3.37). Among patients with baseline CD4 cell counts <200 cells/microL, adherence was the strongest independent predictor of the time to a CD4 cell count >200 cells/microL (RH = 4.85, 95% CI: 3.15-7.47). CONCLUSIONS: These data demonstrate that substantial CD4 gains are possible among highly advanced adherent patients and should contribute to the ongoing debate over the optimal time to initiate HAART.     

Evaluation of Dynabeads and Cytospheres compared with flow cytometry to enumerate CD4+ T cells in HIV-infected Ugandans on antiretroviral therapy

BACKGROUND: Laboratory-based monitoring of antiretroviral therapy is essential but adds a significant cost to HIV care. The World Health Organization 2006 guidelines support the use of CD4 lymphocyte count (CD4) to define treatment failure in resource-limited settings. METHODS: We compared CD4 obtained on replicate samples from 497 HIV-positive Ugandans (before and during ART) followed for 18 months by 2 manual bead-based assays, Dynabeads (Dynal Biotech), and Cytospheres (Beckman Coulter) with those generated by flow cytometry at the Infectious Diseases Institute in Kampala, Uganda. RESULTS: We tested 1671 samples (123 before ART) with Dynabeads and 1444 samples (91 before ART) with Cytospheres. Mean CD4 was 231 cells/mm (SD, 139) and 239 cells/mm (SD, 140) by Dynabeads and flow cytometry, respectively. Mean CD4 was 186 cells/mm (SD, 101) and 242 cells/mm (SD, 136) by Cytospheres and flow cytometry, respectively. The mean difference in CD4 count by flow cytometry versus Dynabeads were 8.8 cells/mm (SD, 76.0) and versus Cytospheres were 56.8 cells/mm (SD, 85.8). The limits of agreement were -140.9 to 158.4 cells/mm for Dynabeads and -112.2 to 225.8 cells/mm for Cytospheres. Linear regression analysis showed higher correlation between flow cytometry and Dynabeads (r=0.85, r=0.73, slope=0.85, intercept=28) compared with the correlation between flow cytometry and Cytospheres (r=0.78, r=0.60, slope=0.58, intercept=45). Area under the receiver operating characteristics curve to predict CD4<200 cells/mm was 0.928 for Dynabeads and 0.886 for Cytospheres. CONCLUSION: Although Dynabeads and Cytospheres both underestimated CD4 lymphocyte count compared with flow cytometry, in resource-limited settings with low daily throughput, manual bead-based assays may provide a less expensive alternative to flow cytometry.     

A reliable and inexpensive EasyCD4 assay for monitoring HIV-infected individuals in resource-limited settings

Serial measurements of absolute CD4+ T-lymphocyte counts are required to initiate and gauge response to therapy and monitor disease progression. Hence, there is an urgent need to evaluate the accuracy and validity of low-cost CD4+ T-cell count assays. Tripotassium EDTA blood specimens from HIV-infected individuals were studied using a novel flow cytometric assay (EasyCD4 assay; Guava Technologies, Hayward, CA) in comparison with standard flow cytometry (FACSCount; Becton Dickinson Immunocytometry Systems, San Jose, CA). The sensitivity, specificity value by EasyCD4 assay in enumerating absolute CD4+ T-cell counts of less than 200 cells/microL were 95% and 100%, respectively. Bland-Altman analysis showed close agreement, with the EasyCD4 assay yielding CD4+ T-cell counts a mean difference of -26 cells/microL (95% confidence interval, -96 to 44 cells/microL) higher than by flow cytometry. Our data suggest that EasyCD4 assay could be a useful alternative assay to conventional flow cytometry, may be appropriate for use in resource-limited settings.     

Herpes zoster in women with and at risk for HIV: data from the Women's Interagency HIV Study

BACKGROUND: Herpes zoster occurs at all CD4 cell counts in HIV-infected adults. It was hypothesized that even in the era of highly active antiretroviral therapy (HAART), zoster risk is higher in HIV-infected than uninfected women. METHODS: Generalized estimating equations modeled self-reported occurrence of zoster between semiannual visits among 1832 HIV-infected and 489 HIV-uninfected women in the Women's Interagency HIV Study followed for up to 7.5 years. RESULTS: A total of 337 (18.4%) HIV-infected and 7 (1.4%) HIV-uninfected women reported zoster at some time during follow-up. Using HIV-infected women with CD4 >750 cells/microL as the reference category, the odds ratios for reporting zoster since the prior visit were: 1.43 (95% CI 0.86-2.37) for CD4 500-749 cells/microL, 2.07 (95% CI 1.27-3.38) for CD4 350-499 cells/microL, 2.72 (95% CI 1.66-4.46) for CD4 200-349 cells/microL, and 3.16 (95% CI 1.92-5.18) for CD4 <200 cells/microL, compared with 0.11 (95% CI 0.046-0.26) for HIV-uninfected women. In multivariate analyses using visits from all HIV-infected women and only those who initiated HAART, lower CD4 cell count was more strongly associated with zoster incidence than were other clinical indicators. CONCLUSIONS: Herpes zoster is associated with degree of immunosuppression in HIV-infected women, but even women with high CD4 counts are at greater risk of zoster than HIV-uninfected women.     

The cost-effectiveness of antiretroviral therapy for treating HIV disease in the Caribbean

BACKGROUND: Antiretroviral therapy (ART) recently became available in the Organization of Eastern Caribbean States (OECS). Survival benefits and budgetary implications associated with universal access to ART have not been examined in the Caribbean. METHODS: Using a state-transition simulation model of HIV with regional data, we projected survival, cost, and cost-effectiveness of treating an HIV-infected cohort. We examined 1 or 2 ART regimens and cotrimoxazole. In sensitivity analysis, we varied HIV natural history and ART efficacy, cost, and switching criteria. RESULTS: Without treatment, mean survival was 2.30 years (mean baseline CD4 count = 288 cells/microL). One ART regimen with cotrimoxazole when the CD4 count was <350 cells/microL provided an additional 5.86 years of survival benefit compared with no treatment; the incremental cost-effectiveness ratio was $690 per year of life saved (YLS). A second regimen added 1.04 years of survival benefit; the incremental cost-effectiveness ratio was $10,960 per YLS compared with 1 regimen. Results were highly dependent on second-line ART costs. Per-person lifetime costs decreased from $17,020 to $9290 if second-line ART costs decreased to those available internationally, yielding approximately $8 million total savings. CONCLUSIONS: In the OECS, ART is cost-effective by international standards. Reducing second-line ART costs increases cost-effectiveness and affordability. Current funding supports implementing universal access regionally over the next year, but additional funding is required to sustain lifetime care for currently infected persons.     

CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment

OBJECTIVES: To determine the rate of CD4 decline and the incidence of opportunistic infections (OIs) among antiretroviral therapy-naive South African HIV-infected patients and inform timing of OI prophylaxis. METHODS: We used mixed-effect models to estimate CD4 cell decline by CD4 cell count strata in HIV-infected patients in the Cape Town AIDS Cohort between 1984 and 2000. Stratum-specific OI incidence per 100 person-years of observation was determined using incidence density analysis. RESULTS: Nine hundred seventy-four patients with 2 or more CD4 cell counts were included. CD4 counts declined by 47.1 cells/microL per year in the stratum with more than 500 cells/microL stratum, 30.6 cells/microL per year in the stratum with 351 to 500 cells/microL, and 20.5 cells/microL per year in the stratum with 201 to 350 cells/microL. Tuberculosis and oral candidiasis were the only OIs that occurred frequently in the stratum with more than 200 CD4 cells/microL. Rates of chronic diarrhea, wasting syndrome, tuberculosis, and oral and esophageal candidiasis increased in the stratum with less than 200 cells/microL, and rates of all OIs were highest in the stratum with 50 cells/microL or less. CONCLUSIONS:: CD4 cell count declines were dependent on CD4 strata and can inform timing of clinic visits and treatment initiation in South Africa. Incidence rates of OIs suggest that targeted OI prophylaxis could prevent substantial HIV-related morbidity in South Africa.     

Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain)

OBJECTIVE: We analyze the factors related to progression to AIDS or death in HIV-infected patients from the Proyecto para la Informatización del Seguimiento Clínico epidemiológico de los pacientes con Infección por VIH/SIDA (PISCIS) Cohort and we assess the optimal time to initiate highly active antiretroviral therapy (HAART) taking lead time into account. METHODS: We selected naive patients who were AIDS-free and initiated HAART after January 1998. Statistical analyses were performed using Cox proportional hazards models. Lead time was defined as the time it took the deferred group with an early disease stage to reach the later stage. The analysis accounting for lead time was performed using multiple imputation methods based on estimates from the pre-HAART period as described elsewhere. RESULTS: Multivariate analysis on 2035 patients (median follow-up = 34.3 months) showed significantly higher hazard ratios (HRs) for a CD4 count <200 cells/microL (HR = 3.79, 95% confidence interval [CI]: 2.18 to 6.57), HIV-1 RNA level >100,000 copies/mL (HR = 1.84, 95% CI: 1.26 to 2.69), and hepatitis C virus (HCV) coinfection (HR = 2.40, 95% CI: 1.65 to 3.49), whereas a lower risk was found for those who started HAART between January 2001 and June 2004 (HR = 0.55, 95% CI: 0.30 to 0.90). When lead time and unseen events were included, we found a higher risk of progression to AIDS among patients who deferred treatment when the CD4 count reached <200 cells/microL (HR = 2.97, 95% CI: 1.91 to 4.63) and 200 to 350 cells/microL (HR = 1.85, 95% CI: 1.03 to 3.33) compared with those who started treatment with CD4 counts from 200 to 350 cells/microL and >350 cells/microL, respectively. CONCLUSIONS: Advanced HIV disease, HCV coinfection, and early HAART period were determinants of AIDS progression or death. Lead-time analysis in asymptomatic HIV-infected patients suggests that the best time to start HAART is before the CD4 count falls to lower than 350 cells/microL.     

Antiretroviral-associated toxicity among HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens

OBJECTIVE: To assess toxicities associated with highly active antiretroviral therapy (HAART) among HIV-1-infected pregnant women treated with nevirapine-based regimens according to Mozambican national guidelines. STUDY DESIGN: Prospective cohort study. METHODS: HIV-1-infected antiretroviral-naive pregnant women with CD4 counts < or =350 cells/microL were initiated on nevirapine, lamivudine, and stavudine or zidovudine and followed monthly. Severe hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > or =5-fold the upper limit of normal. Analyses were stratified by baseline CD4 count (<250 vs. 250-350 cells/microL). RESULTS: Among 146 pregnant women, 75 (52%) began nevirapine, lamivudine, and zidovudine and 71 (48%) began nevirapine, lamivudine, and stavudine. Overall, 79 (54%) women had CD4 counts <250 cells/microL, 7 (5%) had grade II hepatotoxicity, and 4 (3%) had severe (grade III or IV) hepatotoxicity. All 4 women with severe hepatotoxicity had baseline CD4 counts > or =250 cells/microL (P = 0.02). Rates of skin toxicity, anemia, and peripheral neuropathy did not differ by CD4 cell count group. Overall, 12 (8%) women changed or discontinued HAART as a result of drug toxicity. CONCLUSIONS: Severe hepatotoxicity from nevirapine-containing HAART in this cohort of pregnant women was more common at higher CD4 counts (6% vs. 0% among women with CD4 counts > or =250 cells/microL and CD4 counts <250 cells/microL, respectively), suggesting that laboratory monitoring is necessary when administering nevirapine-containing regimens to pregnant women with CD4 counts > or =250 cells/microL.     

Comparison of capillary based microflurometric assay for CD4+ T cell count estimation with dual platform Flow cytometry

The CD4+ T cell count estimation is an important monitoring tool for HIV disease progression and efficacy of anti-retroviral treatment (ART). Due to availability of ART at low cost in developing countries, quest for reliable cost effective alternative methods for CD4+ T cell count estimation has gained importance. A simple capillary-based microflurometric assay (EasyCD4 System, Guava Technology) was compared with the conventional flow cytometric assay for estimation of CD4+ T cell counts in 79 HIV infected individuals. CD4+ T cell count estimation by both the assays showed strong correlation (r = 0.938, p < 0.001, 95% CI 0.90 to 0.96). The Bland Altman plot analysis showed that the limits of variation were within agreeable limits of ± 2SD (-161 to 129 cells/mm³). The Easy CD4 assay showed 100% sensitivity for estimating the CD4+ T cell counts < 200 cells/mm³ and < 350 cells/mm³ and 97% sensitivity to estimate CD4+ T cell count < 500 cells/mm³. The specificity ranged from 82 to 100%. The Kappa factor ranged from 0.735 for the CD4+ T cell counts < 350 cells/mm³ to 0.771 for < 500 cells/mm³ CD4+ T cell counts. The system works with a simple protocol, is easy to maintain and has low running cost. The system is compact and generates minimum amount of waste. Hence the EasyCD4 System could be applied for estimation of CD4+ T cell counts in resource poor settings.     

Total Lymphocyte Count as surrogate marker for CD4 Cell Count in HIV-Infected Individuals in Gondar University Hospital, Northwest Ethiopia

ABSTRACT: BACKGROUND: The high cost of CD4 count estimation in resource-limited countries is a major challenge in initiating patients on highly active antiretroviral therapy (HAART). Therefore, assessment of inexpensive and simple laboratory diagnostic marker is mandatory to diagnose immunosuppression. OBJECTIVE: To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected patients. Materials and Methods In this cross sectional study, 400 ART-naive HIV-positive patients enrolled in Gondar University Hospital, from March 2011 to May 2011, were tested for CD4 count & TLC. The cutoffs were determined as: 200 cells/muL for CD4 count and 1200 cells/muL for TLC by using BD FACS count and CELL DYN 1800 Flow Cytometrys respectively. Spearman correlation between TLC and CD4 cell count were assessed. Sensitivity, specificity, positive and negative predictive values for different age a group, TLC [less than or equal to]1200 was computed for CD4 count [less than or equal to]200 cells/cu.mm. RESULTS: Among 400 ART naive HIV infected patients, 278 (69.5%) were females. The mean age of the study participants was 33.7. TLC and CD4 count were positively correlated (r = 0.33, p = 0.001). A TLC of [less than or equal to]1200 cells/m m3 was found to have a sensitivity (32.86%), specificity (95.33%), PPV (79.7%), and NPV (71.9%) for predicting a CD4 count of <200 cells/mm3. CONCLUSION: This study showed that low sensitivity and specificity of TLC as a surrogate measure for CD4 count. Moreover, CD4 cell counts of < 200 cells/mm3 were found in 96 cases (24%) with TLCs of [less than or equal to]1200 cells/mm3. Thus, 1 in 4 individuals would have been deprived of needed treatment. Therefore, we recommend keep on expansion of access to CD4 counter.     

艾滋病患者外周血淋巴细胞计数取代CD4~+T细胞计数监测HAART疗效

评价血友病合并人类免疫缺陷病毒(HIV)和丙型肝炎病毒(HCV)感染的患者接受高效抗逆转录病毒治疗(highly ac-tive anti-retroviral therapy,HAART)时总淋巴细胞计数(total lymphocyte count,TLC)与CD4+T淋巴细胞计数间的相关性。回顾性分析了61例接受HAART的血友病合并HIV和HCV感染的患者共885对TLC与CD4+T淋巴细胞计数间的相关性。TLC用于预测CD4+T淋巴细胞计数的敏感性、特异性和阳性预侧值分别在不同的TLC范围对应于CD4+T淋巴细胞计数<200个/mm3时和CD4+T淋巴细胞计数<350个/mm3时获得。结果885对TLC与CD4+T淋巴细胞计数间存在相关性(r=0.511,P<001)。TLC<1 600个/mm3对应CD4+T淋巴细胞计数<200个/mm3有62.8%的敏感性、68.1%的特异性、43.1%的阳性预测值;TLC<1 800个/mm3对应CD4+T淋巴细胞计数<350个/mm3有79.1%的敏感性、78.0%的特异性、72.5%的阳性预测值。TLC可以作为一种低廉的监测手段在AIDS患者接受HAART时用于估测CD4+T淋巴细胞计数,其敏感性、特异性和阳性预侧值在TLC<1 800个/mm3对应CD4+T淋巴细胞计数<350个/mm3时最为明显。     

Total lymphocyte count (TLC) is a useful tool for the timing of opportunistic infection prophylaxis in India and other resource-constrained countries

BACKGROUND: In most resource-constrained countries, CD4 cell count testing is prohibitively expensive for routine clinical use and is not widely available. As a result, physicians are often required to make decisions about opportunistic infection (OI) chemoprophylaxis without a laboratory evaluation of HIV stage and level of immunosuppression.OBJECTIVES To evaluate the correlation of total lymphocyte count (TLC), an inexpensive and widely available parameter, to CD4 count. To determine a range of TLC cutoffs for the initiation of OI prophylaxis that is appropriate for resource-constrained settings. METHODS: Spearman correlation between CD4 count and TLC was assessed in patients attending an HIV/AIDS clinic in South India. Positive predictive value (PPV), negative predictive value (NPV), and sensitivity and specificity of various TLC cutoffs were computed for CD4 count <200 cells/mm3 and <350 cells/mm3. Correlation and statistical indices computed for all patients and for patients dually infected with HIV and active tuberculosis. RESULTS: High degree of correlation was noted between 650 paired CD4 and TLC counts (r = 0.744). TLC <1400 cells/mm3 had a 76% PPV, 86% NPV, and was 73% sensitive, 88% specific for CD4 count <200 cells/mm3. TLC <1700 cells/mm3 had a 86% PPV, 69% NPV, and was 70% sensitive, 86% specific for CD4 count <350 cells/mm3. The cost of a single CD4 count in India is approximately 30 US dollars, whereas the cost of a single TLC is 0.80 US dollars. CONCLUSION: TLC could serve as a low-cost tool for determining both a patient's risk of OI and when to initiate prophylaxis in resource-constrained settings. PPV, NPV, sensitivity, and specificity maximally aggregated at TLC <1400 cells/mm3 for CD4 <200 cell/mm3 and TLC <1700 cells/mm3 for CD4 <350 cells/mm3. Selection of appropriate TLC cutoffs for prophylaxis administration should be made on a regional basis depending on OI incidence, antimicrobial resistance patterns, and availability of the antimicrobials.     

Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection

OBJECTIVE: To compare the long-term prognostic significance of different definitions of immunologic and virologic responses to highly active antiretroviral therapy (HAART) at 6 months. METHODS: This was a prospective study conducted in 68 French hospitals. HAART was initiated in 2236 protease inhibitor-naive patients included in the French Hospital Database on HIV. Multivariate Cox proportional hazard models measuring time from 6 months after starting HAART were used to compare the strength of the association between different definitions of immunologic and virologic responses at 6 months and subsequent progression to AIDS or death. The Akaike's Information Criteria were used to identify the most appropriate model. RESULTS: During a median follow-up of 58 months, 325 patients experienced an AIDS-defining event or died. The model that fitted best was the model in which the CD4 cell count and plasma HIV-1 RNA values attained at 6 months were considered. The risk of clinical progression at 5 years ranged from 7% (95% confidence interval [CI]: 4-10) in patients whose CD4 cell count at 6 months was >or=350 cells/microL and whose HIV-1 RNA concentration was <3 log10 copies/mL to 63% (95% CI: 52-75) in patients whose CD4 cell count at 6 months was <100 cells/microL and whose HIV-1 RNA concentration was >or=5 log10. CONCLUSIONS: Plasma HIV-1 RNA concentration and CD4 cell count should be taken into account independently when evaluating early response to treatment. The persistent impact of early response on clinical progression at 5 years emphasizes the major importance of the success of first-line HAART.     

A comparison of genital HIV-1 shedding and sexual risk behavior among Kenyan women based on eligibility for initiation of HAART according to WHO guidelines

BACKGROUND: Guidelines for initiating antiretrovirals are based on markers of advanced disease and are not directly linked to markers of HIV-1 transmission such as viral shedding. METHODS: We evaluated genital HIV-1 shedding and risk behavior among 650 antiretroviral-na?ve women stratified by WHO criteria for initiating antiretrovirals based on CD4 count and symptoms. RESULTS: Genital HIV-1 concentrations increased in stepwise fashion with declining CD4 counts and the presence of symptoms. Compared with the reference group (asymptomatic with CD4 >350 cells/microL), those with advanced immunosuppression (CD4 <200 cells/microL) had significantly higher cervical HIV-1 RNA concentrations (2.4 log10 copies/swab vs. 3.8 log10 copies/swab, P < 0.001). However, women with CD4 counts <200 cells/microL were also less likely than the reference group to report intercourse during the past week (58% vs. 26%, P < 0.001). CONCLUSIONS: Antiretroviral guidelines focusing on individuals with the most advanced immunosuppression will target those with the highest genital HIV-1 concentrations. However, individuals with less advanced immunosuppression also have high levels of genital HIV-1 and may be more sexually active. The effect of increased antiretroviral availability on the spread of HIV-1 might be enhanced by extending treatment, in addition to other risk reduction services, to those with less advanced disease.     

Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022

OBJECTIVE: To compare the safety of nelfinavir and nevirapine-based antiretroviral treatment in HIV-1-infected pregnant women. METHODS: In Pediatric AIDS Clinical Trials Group Protocol 1022, 38 antiretroviral-naive pregnant women at 10-30 weeks' gestation were randomized to nelfinavir or nevirapine with zidovudine plus lamivudine. The study was suspended because of greater than expected toxicity and changes in nevirapine prescribing information. The incidence of treatment-limiting hepatic or cutaneous toxicity was compared between groups for all subjects and for the subset with CD4 cell counts greater than 250 cells/microL at study entry. RESULTS: Toxicity was seen in 1 (5%) of 21 subjects randomized to nelfinavir and 5 (29%) of 17 subjects randomized to nevirapine (P = 0.07). Within the nevirapine group, 1 subject developed fulminant hepatic failure and died, and another developed Stevens-Johnson syndrome. The one adverse event associated with nelfinavir occurred in a subject with a CD4 cell count less than 250 cells/microL. All 5 events among subjects with a CD4 cell count greater than 250 cells/microL were associated with nevirapine (P = 0.04). CONCLUSIONS: Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.     

Evaluation of a low-cost method, the Guava EasyCD4 assay, to enumerate CD4-positive lymphocyte counts in HIV-infected patients in the United States and Uganda

OBJECTIVE: To evaluate the EasyCD4 assay, a less expensive method to enumerate CD4+ lymphocytes, in resource-limited settings. DESIGN: Cross-sectional study conducted in the United States and Uganda. METHODS: We compared CD4+ cell counts obtained on replicate samples from HIV-infected patients by the EasyCD4 assay, a microcapillary flow-based system, and by standard flow cytometry or FACSCount with linear regression and the Bland-Altman method. RESULTS: Two hundred eighteen samples were analyzed (77 in the United States and 141 in Uganda). In the United States, mean +/- SD CD4 was 697 +/- 438 cells/microL by standard flow cytometry and 688 +/- 451 cells/microL by EasyCD4. In Uganda, the mean +/- SD CD4 was 335 +/- 331 cells/microL by FACSCount and 340 +/- 327 cells/microL by EasyCD4. The 2 methods were highly correlated (US cohort, r2 = 0.97, slope = 1.0, intercept = -18; Ugandan cohort, r2 = 0.92; slope = 0.95; intercept = 23). The mean differences in CD4 cell counts were 9.0 and -4.6 cells/microL for the US and Ugandan cohorts, respectively, and they were not significant in either cohort. In the Ugandan cohort, sensitivity and specificity of the EasyCD4 for CD4 below 200 cells/microL were 90% and 98%, respectively. Positive predictive value was 96%; negative predictive value was 93%. CONCLUSIONS: Our results suggest that EasyCD4 may be used with high positive and negative predictive value in resource-limited settings.