Monica Gandhi

Association of Cigarette Smoking With HIV Prognosis Among Women in the HAART Era: A Report From the Women’s Interagency HIV Study

OBJECTIVE We assessed the association of cigarette smoking with the effectiveness of highly active antiretroviral therapy (HAART) among low-income women. METHODS Data were analyzed from the Womens Interagency HIV Study, a multisite longitudinal study up to 7.9 years for 924 women representing 72% of all women who initiated HAART between July 1, 1995, and September 30, 2003. RESULTS When Coxs regression was used after control for age, race, hepatitis C infection, illicit drug use, previous antiretroviral therapy, and previous AIDS, smokers on HAART had poorer viral responses (hazard ratio [HR]=0.79; 95% confidence interval [CI]=0.67, 0.93) and poorer immunologic response (HR=0.85; 95% CI=0.73, 0.99). A greater risk of virologic rebound (HR=1.39; 95% CI=1.06, 1.69) and more frequent immunologic failure (HR=1.52; 95% CI=1.18, 1.96) were also observed among smokers. There was a higher risk of death (HR=1.53; 95% CI=1.08, 2.19) and a higher risk of developing AIDS (HR=1.36; 95% CI=1.07, 1.72) but no significant difference between smokers and nonsmokers in the risk of death due to AIDS. CONCLUSIONS Some of the benefits provided by HAART are negated in cigarette smokers.

Does Patient Sex Affect Human Immunodeficiency Virus Levels

We undertook a critical epidemiological review of the available evidence concerning whether women have lower levels of human immunodeficiency virus (HIV) RNA than do men at similar stages of HIV infection. The 13 studies included in this analysis reported viral load measurements in HIV-infected men and women at a single point in time (cross-sectional studies) or over time (longitudinal studies). Seven of the 9 cross-sectional studies demonstrated that women had 0.13-0.35 log(10) ( approximately 2-fold) lower levels of HIV RNA than do men, despite controlling for CD4(+) cell count. Four longitudinal studies revealed that women had 0.33-0.78 log(10) (2- to 6-fold) lower levels of HIV RNA than do men, even when controlling for time since seroconversion. Adjustment for possible confounders of the relationship between sex and viral load, including age, race, mode of virus transmission, and antiretroviral therapy use, did not change this outcome. This finding is significant, because viral loads are frequently used to guide the initiation and modification of antiretroviral therapy.

Effects of treated and untreated depressive symptoms on highly active antiretroviral therapy use in a US multi-site cohort of HIV-positive women

Abstract This study examines the effects of treated and untreated depressive symptoms on the likelihood of utilization of highly active antiretroviral therapy (HAART) among a multi-site cohort of HIV-infected women who screened positive for probable depression. Data were collected biannually from 1996 through 2001 in a prospective cohort study. Random-effects regression analysis was used to estimate the longitudinal effects of mental health treatment on the probability of HAART utilization, controlling for clinical indicators (CD4 count, viral load), demographic features (race/ethnicity, income), and behavioural factors (recent crack, cocaine, or heroin use). Use of antidepressants plus mental health therapy, or use of mental health therapy alone significantly increased the probability of HAART utilization, compared to receiving no depression treatment. Use of antidepressants alone did not differ significantly from receiving no depression treatment. African American women and those who used crack, cocaine, or heroin also were less likely to use HAART. These findings suggest that efforts to enhance depressed womens access to psychopharmacologic treatment and therapy may increase their use of the most effective HIV therapies.

Atazanavir Concentration in Hair Is the Strongest Predictor of Outcomes on Antiretroviral Therapy

BACKGROUND Adequate exposure to antiretrovirals is important to maintain durable responses, but methods to assess exposure (eg, querying adherence and single plasma drug level measurements) are limited. Hair concentrations of antiretrovirals can integrate adherence and pharmacokinetics into a single assay. METHODS Small hair samples were collected from participants in the Womens Interagency HIV Study (WIHS), a large cohort of human immunodeficiency virus (HIV)-infected (and at-risk noninfected) women. From 2003 through 2008, we analyzed atazanavir hair concentrations longitudinally for women reporting receipt of atazanavir-based therapy. Multivariate random effects logistic regression models for repeated measures were used to estimate the association of hair drug levels with the primary outcome of virologic suppression (HIV RNA level, <80 copies/mL). RESULTS 424 WIHS participants (51% African-American, 31% Hispanic) contributed 1443 person-visits to the analysis. After adjusting for age, race, treatment experience, pretreatment viral load, CD4 count and AIDS status, and self-reported adherence, hair levels were the strongest predictor of suppression. Categorized hair antiretroviral levels revealed a monotonic relationship to suppression; women with atazanavir levels in the highest quintile had odds ratios (ORs) of 59.8 (95% confidence ratio, 29.0-123.2) for virologic suppression. Hair atazanavir concentrations were even more strongly associated with resuppression of viral loads in subgroups in which there had been previous lapses in adherence (OR, 210.2 [95% CI, 46.0-961.1]), low hair levels (OR, 132.8 [95% CI, 26.5-666.0]), or detectable viremia (OR, 400.7 [95% CI, 52.3-3069.7]). CONCLUSIONS Antiretroviral hair levels surpassed any other predictor of virologic outcomes to HIV treatment in a large cohort. Low antiretroviral exposure in hair may trigger interventions prior to failure or herald virologic failure in settings where measurement of viral loads is unavailable. Monitoring hair antiretroviral concentrations may be useful for prolonging regimen durability.

Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting

Background:In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure. Methods:We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study. Results:Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 μg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair. Conclusions:Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Prevalence of Clinical Symptoms Associated with Highly Active Antiretroviral Therapy in the Women's Interagency HIV Study

BACKGROUND The extended use of antiretroviral drugs among human immunodeficiency virus (HIV)-seropositive individuals underscores the need for a comprehensive evaluation of therapy-associated clinical symptoms. METHODS Beginning in April 2000, 364 HIV-seronegative and 1256 HIV-seropositive women enrolled in a multicenter cohort study reported clinical symptoms that included abdominal pain, diarrhea, anorexia, nausea and/or vomiting, myalgias, fatigue, fever, body fat redistribution, dizziness, headaches, paresthesias, xerostomia, nephrolithiasis, and rash. We examined the prevalence of symptoms with respect to HIV infection and the use of highly active antiretroviral therapy (HAART), using data-correlation models. RESULTS In the 6 months before a study visit, 49% of HIV-seronegative women, 67% of HIV-seropositive women not receiving therapy, and 69% of HIV-seropositive women receiving HAART reported any clinical symptom. The odds ratios (ORs) for reporting any symptom were 1.4 (95% confidence interval [CI], 1.1-1.8) for women who changed HAART regimens and 0.9 (95% CI, 0.7-1.1) for women reporting stable HAART use, compared with those reporting no therapy use. Significant findings (P<.05) for particular symptoms were an increased odds of diarrhea, nausea and/or vomiting, body fat redistribution, myalgias, and paresthesias, when data for women who changed HAART regimens were compared with those for women not receiving therapy. The OR for reporting any symptom was 1.5 (95% CI, 1.2-1.9) for women who switched HAART regimens and 1.6 (95% CI, 1.3-1.9) for women who discontinued HAART, compared with those reporting stable HAART use. CONCLUSIONS Our findings confirm the high prevalence of clinical symptoms among HIV-seropositive women who changed HAART regimens. The high prevalence of symptoms among HIV-seronegative women and HIV-seropositive women not receiving therapy demonstrates that caution should be used when attributing the occurrence of symptoms entirely to HAART.

Protease inhibitor levels in hair strongly predict virologic response to treatment.

Objective:Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. The currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months, and may provide a novel method for predicting therapeutic responses. Design/methods:The Womens Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly prescribed protease inhibitors (lopinavir/ritonavir and atazanavir) in small hair samples. We examined the association between hair protease inhibitor levels and initial virologic responses to therapy in multivariate logistic regression models. Results:ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new protease inhibitor-based regimen. For participants initiating lopinavir/ritonavir, the odds ratio (OR) for virologic suppression was 39.8 [95% confidence interval (CI) = 2.8–564] for those with lopinavir hair levels in the top tertile (>1.9 ng/mg) compared to the bottom (≤0.41 ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4 cell count, and prior experience with protease inhibitors. For women starting atazanavir, the adjusted OR for virologic success was 7.7 (95% CI = 2.0–29.7) for those with hair concentrations in the top tertile (>3.4 ng/mg) compared to the lowest (≤1.2 ng/mg). Conclusion:Protease inhibitor levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This non-invasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.

Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084.

Sensitive analysis of anti‐HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry

A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode. This method was validated from 0.01 to 4.0 ng/mg hair for ritonavir and 0.05-20 ng/mg hair for lopinavir and efavirenz by using 2 mg of a human hair sample. The interday and intraday assay precision (coefficients of variation, CV) for spiked quality control (QC) samples at low, medium and high concentrations were within 15% and accuracy ranged from 89% to 110%. Assay reproducibility was also demonstrated by analysis of incurred hair QC samples (CV <14%). No significant matrix ionization suppression was observed. This developed method allowed for the monitoring of these target medications in the hair samples of HIV-infected women on antiretroviral therapy in an observational study using small amounts of hair.

Common clinical conditions-age, low BMI, ritonavir use, mild renal impairment-affect tenofovir pharmacokinetics in a large cohort of HIV-infected women

Objective:Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world settings are unknown. Design:Intensive pharmacokinetic studies of tenofovir in a large, diverse cohort of HIV-infected women over 24 h at steady state were performed and factors that influenced exposure [assessed by areas under the concentration–time curves (AUCs)] identified. Methods:HIV-infected women (n = 101) on tenofovir-based therapy underwent intensive 24-h pharmacokinetic sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight, and BMI were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFRs) prior to starting tenofovir were estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using both creatinine and cystatin-C measures. Results:The median (range) of tenofovir AUCs was 3350 (1031–13 911) ng × h/ml. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, P = 0.002), increasing age (1.21-fold increase per decade, P = 0.0007), and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70 ml/min, P = 0.0075). Conclusion:Concomitant ritonavir use, increasing age, decreasing BMI, and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.