Cross-validation of a high-performance liquid chromatography nevirapine plasma assay in a resource-limited setting in Zimbabwe

An international HIV pharmacology specialty laboratory (PSL) was established at the University of Zimbabwe to increase bioanalytical and investigator capacities. Quantitation of plasma nevirapine in samples from the AIDS Clinical Trials Group protocol 5279 was compared between the University of Nebraska Medical Center PSL and the University of Zimbabwe PSL. Both PSLs employed internally developed methods utilising reverse-phase high-performance liquid chromatography with ultraviolet detection. Eighty-seven percent of the cross-validation results exhibited ± 20% difference.

Urine Lipoarabinomannan Testing in Adults With Advanced Human Immunodeficiency Virus in a Trial of Empiric Tuberculosis Therapy

Background The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear. Methods The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen–negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method. Results A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9–32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04). Conclusions Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence.

Baseline neurocognitive impairment (NCI) is associated with incident frailty but baseline frailty does not predict incident NCI in older persons with HIV

Background Neurocognitive impairment (NCI) and frailty are more prevalent among persons with HIV (PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well-established. Setting AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. Methods ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. Results 929 participants were included with a median age of 51 years (IQR 46-56). At study entry, 16% had NCI and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR]=2.06; 95% confidence interval [CI]=0.94, 4.48; p=0.07). Further adjustment for confounding strengthened this association (OR=2.79; 95% CI=1.21, 6.43; p=0.02). Baseline frailty however was not associated with NCI development. Conclusions NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

Reduction of Maternal–Infant Transmission of HIV Type 1 With Zidovudine Treatment

This article summarizes the landmark results of Pediatric AIDS Clinical Trials Group Protocol 076. Pregnant women between 14 and 34 weeks with a CD4 count above 200 and no indication for antiretroviral therapy were randomized to zidovudine treatment or placebo. Zidovudine was shown to reduce HIV transmission from mother to child by 67.5%. Zidovudine treatment was not associated with neonatal death, premature birth, fetal growth or structural abnormalities. The majority of maternal adverse effects were obstetric complications that were not associated with either placebo or intervention groups. It reviews study design, findings, and limitations. This study is then situated in historical context and in reference to current guidelines.

Pretomanid Pharmacokinetics in the Presence of Rifamycins: interim Results from a Randomized Trial among Patients with Tuberculosis

Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and if it can be used together with rifamycins, key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, pyrazinamide, plus either rifampin or rifabutin versus standard of care under fed conditions and the AIDS Clinical Trials Group (ACTG) 5306 trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reduction in pretomanid AUC compared to rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in APT and A5306, respectively. Median Cmax in the rifampin and rifabutin arms were 2.14 and 3.35 mg/liter, while median AUC0-24h were 30.1 and 59.5 mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high, but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin.

The Bio/Necropolitics of ACTG 076: Lessons from Pregnant Women of Colour Living with HIV for Treatment for Prevention in the Twenty-first Century

Since the pharmaceutical turn, using HIV treatment to prevent transmission is increasingly common. Treatment as Prevention®, or TasP, has relied on HIV treatment to prevent HIV transmission, targeting people living with HIV. However, TasP is predicated on troublesome heterosexist, classist, and racist medical practices borrowed from various times and spaces that enact biopolitical and necropolitical relations. This paper discusses the debate surrounding the first clinical trial that used HIV treatment to prevent transmission from woman-to-foetus. The 1994 landmark AIDS Clinical Trials Group 076 study laid the groundwork for using HIV treatment to prevent HIV transmission, the essential precursor to TasP. By examining the concerns of HIV positive women of colour and other AIDS activists, we are able to understand the ethical dilemmas and practical consequences that still haunt today's game-changing uses of HIV treatment for prevention and to see how biopolitics and necropolitics persist in TasP.

Maybe the End of HIV

This chapter focuses on HIV, which has been our most politically charged illness and a defining health challenge of our time. The world of HIV care over the last two decades has seen a great, almost miraculous, revolution. Today, a 35-year-old who was HIV-infected in 2018 and takes her daily medication adherently has the life expectancy of a 35-year-old without HIV infection. Monthly injections of long-acting HIV drugs look to be as good as daily pills at suppressing the virus, creating easier treatment. Despite these stunning advances, disparities in detection and care characterize the disease. The epidemic has shifted to groups that are hard to test, hard to get started on preventive care, and hard to keep on daily medication—persons who inject stimulants, men on the down-low, the mentally ill, the homeless, and the rural poor with no health insurance. Lack of information, lack of trust of providers, unfamiliarity with services, and refusals of testing and treatment due to social rejection and privacy concerns make the delivery of care more challenging for these groups. Even among persons enrolled in AIDS clinical trials who have found their way to cutting-edge medical treatment, blacks and Hispanics have poorer outcomes. As such, reaching an end to HIV will require new attention to health systems and social stigma, to geography, to housing and outreach, to the long work of public health.