From Exposures to Population Interventions: Pregnancy and Response to HIV Therapy

Many epidemiologic studies identify contrasts between an “always-exposed” population and a “never-exposed” population. Such “exposure effects” are perhaps most valuable in discussing individual lifestyle changes, or in clinical care; they may be less valuable in estimating the potential effects of realistic public health interventions. Various methods, among them population attributable fractions and generalized impact fractions, attempt to obtain more policy-relevant estimates of “population intervention” effects, but such methods remain rare in the epidemiologic literature. Here, we describe the use of the parametric g-formula as a tool for the estimation of population intervention effects in longitudinal data. Our discussion is motivated by a previous study of the effect of incident pregnancy on time to virological failure among human immunodeficiency virus-positive women initiating antiretroviral therapy in South Africa between 2004 and 2011. We show that 1) interventional estimates of effect can be estimated in longitudinal data using the parametric g-formula and 2) exposure effects and population interventional effects can have dramatically different interpretations and magnitudes in real-world data. Epidemiologists should consider estimating interventional effects in addition to exposure effects; doing so would allow the results of epidemiologic studies to be more immediately relevant to policy-makers and to implementation science efforts

From Patients to Policy: Population Intervention Effects in Epidemiology

Interest in implementation science and recent calls for consequentialist epidemiology urge epidemiologists to produce work more immediately applicable to public health practice. A clear vocabulary for such approaches is lacking. Here, we present a potential taxonomy of causal effects, distinguishing between “exposure effects” more relevant to patients and individuals; and “population intervention effects” more relevant to public health policy. We discuss this range of effects using figures and a simple numerical example

HIV, antiretroviral therapy, and tuberculosis: outcomes in Johannesburg, South Africa

The rollout of highly active antiretroviral therapy (HAART) in sub-Saharan Africa poses many challenges. In one of the largest HAART clinics in Africa, we described overall outcomes of HAART, the impact of treated pulmonary tuberculosis (PTB) at the time of HAART initiation on all-cause mortality, and the impact of prevalent and incident tuberculosis treatment on the risk of the substitution of the antiretroviral drug stavudine. In these analyses, robust methods including inverse probability weighted marginal structural models were used where appropriate to control for confounding and bias due to losses to follow-up and competing risks. This analytic approach made these results more robust compared with more "traditional" analyses. Relatively few patients died after HAART initiation. Risk of death during follow-up increased in individuals who at baseline were older or had low CD4 cell counts, low body mass index, low hemoglobin, or advanced disease stage. The crude hazard ratio (HR) for the effect of treated PTB at time of HAART initiation on mortality was 1.71 (95% confidence interval [CI] 1.31-2.23) and the adjusted HR was 1.06 (95% CI 0.75-1.49), a difference due to the fact that individuals with PTB at time of HAART initiation had more severe immunodepression. Additionally, individuals who started HAART within 30 days of initiation of treatment for PTB were not at higher risk of death than other individuals, suggesting that early HAART initiation can be safely recommended. In analysis of the effect of treatment for pulmonary or extrapulmonary tuberculosis (TB) on risk of stavudine substitution, we found that if TB treatment is ongoing at the time of initiation of HAART, there was between a two- and sevenfold increase in risk of stavudine substitution during the early months of HAART. However, incident TB treatment after HAART initiation, did not raise the risk of stavudine substitution. These results were robust to sensitivity analysis, and suggest that the use of stavudine might be reconsidered in patients receiving treatment for TB. Overall, these results suggest that early initiation of HAART is warranted in patients with TB, but that clinicians need to monitor these patients closely for indications for stavudine substitution

Hormonal contraceptive methods and risk of HIV acquisition in women : a systematic review of epidemiological evidence

Peer reviewedPublisher PD

Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating HAART in South Africa

<p>Abstract</p> <p>Background</p> <p>As stavudine remains an important and widely prescribed drug in resource-limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question.</p> <p>Methods</p> <p>We analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six- and/or 12-month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression.</p> <p>Results</p> <p>Between 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13-2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86-5.25), lipoatrophy (OR 11.8; 95% CI 3.2-43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83-18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates.</p> <p>Conclusions</p> <p>Lower stavudine dosage is associated with fewer reports of several stavudine-associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART.</p

Propensity score estimation: neural networks, support vector machines, decision trees (CART), and meta-classifiers as alternatives to logistic regression

Propensity scores for the analysis of observational data are typically estimated using logistic regression. Our objective in this Review was to assess machine learning alternatives to logistic regression which may accomplish the same goals but with fewer assumptions or greater accuracy

Tuberculosis in Patients Receiving Antiretroviral Treatment: Incidence, Risk Factors, and Prevention Strategies

To determine tuberculosis (TB) incidence rates and risk factors among individuals receiving antiretroviral treatment (ART)

Pregnancy and Virologic Response to Antiretroviral Therapy in South Africa

Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART.We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤ 400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results.Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate