Chloroquine Administration in Breastfeeding Mothers Associates with Increased HIV-1 Plasma Viral Loads

2Abstract Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been proposed to be effective at treating COVID-19 patients. We, and others, have previously reported on the capacity of CQ to reduce HIV-1 replication in vitro. We tested CQ administration in post-partum mothers on influencing HIV-1 viral loads in human milk as a means of lowering mother to child transmission. A Phase I/II, randomized, placebo-controlled study to evaluate chloroquine administration to reduce HIV-1 RNA levels in human milk: the CHARGE study. Thirty HIV-1 positive pregnant Rwandese women (CQ n = 20; placebo n = 10) were enrolled in a 16-week study, with the treatment group receiving a 200 mg oral dose of CQ daily. Base-line plasma viral load (pVL) measurements and CD4 counts were determined prior to delivery, and pVL, breast milk VL (bmVL) and CQ levels measured during treatment. For women receiving treatment, CQ concentration was higher in breast milk compared to plasma (over 2.5-fold), with a positive correlation between the levels in the two compartments (P < 0.003). A link between high CQ concentrations in plasma and high CD4 counts (P < 0.001) was observed. Surprisingly, we found a significant increase in pVL after CQ treatment in over half of the mothers (n=11; P < 0.001) and with no alteration to bmVL measurements. No specific amino acid alterations in the gp120 envelope sequences could be associated with CQ administration. CQ usage is associated with a significant increase to pVL in early breastfeeding mothers from Rwanda which cautions against the use of CQ in such individuals. Our results highlight a discrepancy between CQ effects on modulating HIV-1 replication in vitro versus in vivo and indicate caution when prescribing CQ to post-partum HIV-1 untreated mothers. This discrepancy should be taken into consideration when testing CQ or HCQ treatment in COVID-19 clinical trials, especially relating to the post-partum setting

Costs of cardiovascular disease prevention care and scenarios for cost saving: a micro-costing study from rural Nigeria.

OBJECTIVE: To assess the costs of cardiovascular disease (CVD) prevention care according to international guidelines, in a primary healthcare clinic in rural Nigeria, participating in a health insurance programme. METHODS: A micro-costing study was conducted from a healthcare provider perspective. Activities per patient per year (e.g., consultations, diagnostic tests) were based on clinical practice in the study clinic. Direct (e.g., staff, drugs) and indirect cost items (overheads) for each activity were measured. A cohort study, patient and staff observations, and interviews in the study clinic provided patient resource utilization data. Univariate sensitivity analyses were performed. Scenario analyses evaluated cost-saving options. The main outcome was the costs of CVD prevention care per patient per year. RESULTS: The costs of CVD prevention care were United States dollars (USD) 144 (range 130-158) per patient per year. Direct costs were USD 82 and indirect costs were USD 62. The main cost drivers were drugs (USD 39) and diagnostic tests (USD 36). The costs of hypertension care were USD 118 (107-132) and that of diabetes care USD 263 (236-289) per patient per year. A combination of task-shifting from doctors to nurses, reduction of appointment frequencies, and minimal organ damage screening would result in a direct cost reduction of 42%. CONCLUSION: This is the first study to report the costs of CVD prevention care in sub-Saharan Africa, based on prospectively collected operational data. The costs observed in our study are unaffordable in many countries in sub-Saharan Africa, highlighting the need for innovative financing mechanisms to fund CVD prevention care

Mortality and progression to AIDS after starting highly active antiretroviral therapy.

OBJECTIVES: To examine survival and progression to AIDS among HIV-infected patients after starting highly active antiretroviral therapy (HAART). METHODS: The study population consisted of 3724 patients from the ATHENA observational cohort who initiated HAART. We considered progression to either an AIDS-defining disease or death, distinguishing HIV-related and non-related (including therapy-related) deaths. A time-dependent multivariate hazards model was fitted to the patient data and 5-year survival probabilities under various therapy scenarios estimated. RESULTS: A total of 459 patients developed AIDS and 346 died during 12 503 person-years of follow-up. HIV-related mortality decreased from 3.8 to 0.7 per 100 person-years between 1996 and 2000 whereas non-HIV-related mortality did not change (0.4 and 0.9, respectively, P = 0.25). For asymptomatic and symptomatic therapy naive patients younger than 50 years with CD4 counts above 10 x 10(6) and 150 x 10(6) cells/l, respectively, predicted 5-year survival probabilities were above 90% when HAART was used continuously. This limit was 450 x 10(6) cells/l when HAART was used during 20 weeks in each 24 week-period of follow-up, and 110 x 10(6) cells/l when patients delayed initiation of HAART for 1 year after becoming eligible for treatment. CONCLUSIONS: Survival probabilities were high among HIV-infected patients initiating HAART at an early stage of infection. The best therapy strategy is therefore to start HAART at this stage of infection. However, deferring HAART in patients with high CD4 cell counts may be clinically more appropriate given toxicity and adherence problems. The lack of any change in non-HIV-related mortality suggests that toxicity has not yet become a major risk factor for death

Viral Decay Dynamics in HIV-Infected Patients Receiving Ritonavir-Boosted Saquinavir and Efavirenz With or Without Enfuvirtide: A Randomized, Controlled Trial (HIV-NAT 012)

The availability of enfuvirtide enables assessment of whether human immunodeficiency virus (HIV) decay can be enhanced by targeting reverse transcriptase, protease, and fusion. We performed a 12-week study of 22 patients randomized to receive ritonavir-boosted saquinavir and efavirenz with (the 3-target arm) or without (the 2-target arm) enfuvirtide. We observed no difference in the mean \pm SD elimination-rate constant for overall decay ( 0.142 \pm 0.040 per day and 0.128 \pm 0.033 per day in the 2- and 3-target arms, respectively; P>.1) or for modeled first-phase decay rate ( -0.62 \pm 0.34 per day and -0.51 \pm 0.16 per day; P >.1). Antiretroviral therapy that inhibits HIV reverse transcriptase and protease exerts potent antiviral effects that might not be augmented by the addition of an HIV fusion inhibitor

Safety and efficacy of once-daily nevirapine dosing : a multicohort study

BACKGROUND: Nevirapine (NVP) is often prescribed once daily in clinical practice in combination with a once daily nucleoside backbone. We investigated the relationship of NVP dosing with safety and efficacy. METHODS: Patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study, Canadian HAART Observational Medical Evaluation and Research (HOMER) cohort and Swiss HIV Cohort Study (SHCS) using NVP-based combination therapy either once daily or twice daily were included. Risk factors for discontinuing NVP because of hypersensitivity reactions (HSRs) were investigated using multivariate logistic regression. Risk factors for virological failure 96 weeks after NVP initiation were identified using logistic regression and Cox models. RESULTS: Of 5,636 patients (774 once daily and 4,862 twice daily), 268 (4.8%) discontinued NVP because of HSR between 2 and 18 weeks. Logistic regression showed that, compared with patients with detectable HIV type-1 (HIV-1) RNA starting twice-daily NVP, there was a significantly higher risk of discontinuation of once-daily NVP because of HSR in patients with detectable HIV-1 RNA at the start of NVP (odds ratio [OR] 1.52; P=0.04), whereas the risk was actually significantly lower in patients starting once-daily NVP with undetectable HIV-1 RNA (OR 0.44; P=0.04). Cox models showed that risk of virological failure was not different for twice- versus once-daily NVP in treatment-naive patients (twice-daily versus once-daily hazard ratio [HR] 1.01; P=0.95), treatment-experienced patients experiencing treatment failure (twice-daily versus once-daily HR 1.22; P=0.30) or patients with undetectable HIV-1 RNA simplifying treatment with NVP (twice-daily versus once-daily HR 1.29; P=0.30). CONCLUSIONS: Initiation of a once-daily NVP-based regimen in patients with suppressed viraemia carries a low risk of treatment-limiting HSR. Once- or twice-daily NVP-based regimens appear to have similar antiretroviral efficacy