Infectious Disease Alert Updates
March 1, 2022 6 minutes read
By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
Delayed HIV Diagnosis with Injectable PrEP
SOURCE: Marzinke MA, Grinsztejn B, Fogel JM, et al. Characterization of human immunodeficiency virus (HIV) infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J Infect Dis 2021;224:1581-1592.
The use of daily tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) for preexposure prophylaxis (PrEP) has been associated with delays in the recognition of human immunodeficiency virus (HIV) infection, mostly owing to delays in HIV antibody production and ongoing suppression of HIV infection, with the consequent development of resistance to TDF and FTC in those acquiring unrecognized HIV infection during treatment.
These authors examined similar breakthrough infections during investigation of long-acting injectable cabotegravir (CAB-LA), an HIV integrase strand transfer inhibitor (INSTI), in the context of a recent HIV prevention trial. HTPN 083 is an ongoing Phase II/III HIV prevention trial comparing CAB-LA vs. TDF/FTC for HIV PrEP in 4,566 eligible persons (men who have sex with men and trans women who have sex with men) enrolled at 43 different sites in the United States. This is a double-blind, double-dummy trial with a five-week lead-in of oral therapy, followed by 148 weeks of injections, and a 48-week tail. The study recently was unblinded, demonstrating a 66% reduction in HIV incidence in the CAB arm relative to the TDF/FTC arm. All of the participants had a negative HIV ribonucleic acid (RNA) test within 14 days of enrollment. Rapid HIV and HIV Ag/Ab tests were obtained, and retrospectively, HIV RNA testing was performed, with additional testing done to detect the timing of HIV infection. Drug levels were measured on dried blood spots, and HIV resistance was determined using GenoSurePRIme assay.
Retrospectively, a total of 58 breakthrough infections were identified as occurring during the blinded portion of the study, including seven infections occurring at the time of enrollment (four in the CAB arm and three in the TDF/FTC arm), and 51 acquired during the study (12 in the CAB arm and 39 in the TDF/FTC arm). The diagnosis of HIV infection was delayed in seven of 12 cases in the CAB arm a median of 98 days (35-185 days) and would have been identified in five of seven cases with viral load testing. In addition, the four baseline infections in the CAB arm would have been detected with viral load testing at the first HIV-positive visit.
Three of the 12 breakthrough infections were found to have occurred during the five-week oral lead-in to the study (two of these had documentation of blood levels ≥ 8 × the 90% CAB inhibitory concentration of drug, and one had none detected); five occurred during a period of no CAB injections or ≥ 6 months after the last CAB injection; and another four infections were acquired despite compliance with the injectable regimen and documentation of blood levels ≥ 8 × the 90% CAB inhibitory concentration of drug. These latter four participants had two to seven CAB injections before their first HIV-positive visit. Thus, six of 12 participants with breakthrough infection in the CAB arm had CAB drug levels that were expected to be protective at the time of HIV infection.
INSTI resistance mutations were detected in five of 14 cases (36%) in the CAB arm that had available genotyping data, and all five reflected different patterns of mutations. Two of these were acquired during treatment, despite on-time CAB-LA injections. A third participant with baseline infection developed INSTI resistance after receiving one CAB-LA infection.
In the TDF/FTC arm, the diagnosis of HIV infection was delayed in three of three baseline infections by a median of 34 (14-36) days, and seven of 39 infections acquired during treatment were delayed by a median of 31 (7-68) days. Viral load testing would have detected infection in the three baseline cases at entry to study, and in six of seven infections at the first positive visit. Low or undetectable drug concentrations were observed in 37 of 39 cases in the TDF/FTC arm, consistent with suboptimal adherence to the regimen. Only two cases were considered “true” breakthrough infections, with adequate drug blood concentrations demonstrated.
Delays in the detection of HIV infection occurred in both arms of the study, although these were generally longer in the injectable CAB-LA arm, with a longer period of delayed antibody detection and viral suppression. In contrast, most cases of acute HIV infection occurring in the TDF/FTC arm would have been detected at the first or next monthly visit. Routine HIV viral load testing both at initiation of CAB-LA treatment and during treatment may help to identify HIV infection and prevent the development of INSTI mutations. However, longer durations between checkups in the “real world” than done in the context of a research study may risk further delays in identifying breakthrough infections and an increased risk of HIV genotypic resistance.
Fatal Wave of COVID-Associated Mucormycosis
SOURCES: Gandra S, Ram S, Levitz SM. The “black fungus” in India: The emerging syndemic of COVID-19-associated mucormycosis. Ann Intern Med 2021;174:1301-1302.
Aranjani JM, Manuel A, Razack HIA, et al. COVID-19-associated mucormycosis: Evidence-based critical review of an emerging infection burden during the pandemic’s second wave in India. PLOS Negl Trop Dis 2012;15:e0009921.
The twin epidemics of diabetes and COVID-19 infection met with devastating consequences in India in May-July 2021, with a surge in COVID-associated mucormycosis infection. India has one of the highest rates of diabetes mellitus (DM) of any developing country, with approximately 65 million adults living with DM. In 2019, prior to the appearance of COVID, the reported case rate of mucormycosis in India was 70 times higher than reported globally. However, during the second large wave of COVID-19 in May-July 2021, there was an unexpected concurrent surge in COVID-associated mucormycosis, with an estimated 40,000 cases occurring throughout 24 different Indian states by July 2021, representing about 0.2% of all hospitalizations. The surge in COVID cases crippled the healthcare system, with shortages of hospital and critical care beds, oxygen, and healthcare workers and physicians. In addition, many hospitals suddenly found themselves facing shortages of amphotericin B.
The majority of patients presented with rhino-orbital infection, although a smaller number had pulmonary mucormycosis. One journal author described the symptoms at presentation in decreasing order of frequency: orbital/facial pain (23%), orbital edema (21%), vision loss (19%), ptosis (11%), and nasal congestion (9%); pulmonary cases presented with fever, cough, and dyspnea and were difficult to distinguish from COVID infection. During the COVID surge, mortality from mucormycosis increased to ~85%, although one published series reported 100% mortality.
The reason for this unexpected surge in co-fungal/COVID infections likely is multifactorial, including the growing population of people with diabetes, many of whom have poor glucose control; excessive and inappropriate use of glucocorticoids for COVID treatment; the misuse of antibiotics for COVID treatment (an excess of 120 million doses of antibiotics were attributed to COVID, including 6.2 million courses of azithromycin); environmental factors; and the hot and humid weather. Since this surge of mucor infections was reported in India, other countries, including France, Italy, Iran, Iraq, Egypt, and Brazil, have reported an increase in COVID-associated mucor infections.
The Indian Health Ministry published guidance for the management of mucormycosis in May 2021, and since then, several countries have made guidelines available online. These guidelines urge a reduction in the use of corticosteroids for COVID infection, better recognition and management of diabetes, and improved supply chains for amphotericin B. Most importantly, they urge early detection and prompt and aggressive surgical intervention for mucor cases. One author warned: “Not all sinus congestion is COVID!”
Delayed HIV Diagnosis with Injectable PrEP; Fatal Wave of COVID-Associated Mucormycosis
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