Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Objective: Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design: We administered a microdose (100 μg) of [superscript 14]C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4[superscript +] cells were measured by accelerator mass spectrometry. Results: The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg–300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4[superscript +] cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4[superscript +] cells and PBMCs. Conclusions: Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.Johns Hopkins University (Institute for Clinical and Translational Research CTSA Grant UL1-RR025005

The potential role of long-acting injectable cabotegravir-rilpivirine in the treatment of HIV in sub-Saharan Africa : a modelling analysis

BACKGROUND: The use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction. METHODS: We used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective. FINDINGS: In our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of$120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced. INTERPRETATION: Our modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives. FUNDING: Bill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655)

Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists

Factors Associated With CD8+ T-Cell Activation in HIV-1–Infected Patients on Long-term Antiretroviral Therapy

BackgroundAbnormal levels of CD8 T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious.MethodsCD8 T-cell activation (% coexpressing CD38/HLA-DR) was analyzed on blood specimens from 833 HIV-1-infected patients on ART for ≥96 weeks with concurrent plasma HIV RNA (vRNA) ≤200 copies per milliliter. Factors associated with CD8 T-cell activation were assessed using generalized estimating equations to incorporate longitudinal measurements (median 4/participant).ResultsParticipants were 84% men, 47% white, 28% black, and 22% Hispanic, with median pre-ART age 38 years and median ART exposure 144 weeks. CD8 T-cell activation was higher at timepoints when vRNA was 51-200 versus ≤50 copies per milliliter [mean CD8 T-cell activation 23.4% vs. 19.7%; adjusted difference: 1.7% (95% confidence interval: 0.1 to 3.4), P = 0.042]. Restricting to vRNA ≤50 copies per milliliter, multivariable models showed the following factors associated with higher CD8 T-cell activation: older age [≥45 vs. ≤30 years: 3.6% (1.4 to 5.7), P = 0.004], hepatitis C virus antibody positivity [3.6% (0.9 to 6.2), P = 0.032], Hispanic vs. white [7.2% (5.3 to 9.0), P < 0.001], lower concurrent CD4 count [≤200 vs. >500 cells/mm: 2.2% (0.7 to 3.7), P < 0.001], lower concurrent CD4/CD8 ratio [-2.6% (-3.7 to -1.5) per 0.5 unit increase, P < 0.001], and higher pre-ART CD8 T-cell activation [2.0% (1.6 to 2.5) per 10% higher, P < 0.001].ConclusionsIn participants included in our analysis, residual low-level viremia between 51 and 200 copies per milliliter during ART was shown to be associated with greater CD8 T-cell activation than full suppression to <50 copies per milliliter. Older age, hepatitis C virus antibody positivity, race/ethnicity, higher pre-ART CD8 T-cell activation, and lower concurrent CD4/CD8 ratio and CD4 T-cell count also contribute to greater CD8 T-cell activation during suppressive ART