Bisher AKIL, MD

Archive for the ‘HIV’ Category

mRNA Vaccine for HIV ?

In HIV on January 11, 2022 at 11:01 pm

“Messenger RNA, or mRNA, is a molecule that tells the body how to make proteins. Vaccines based on mRNA are newly available to the public. These vaccines instruct our cells to make certain proteins from a virus or other microbe. These harmless pieces can trigger the body’s immune response. That immune response produces antibodies and cells that help protect against getting infected if the real virus enters the body. This technology was used to develop and license two FDA approved COVID vaccines. But researchers have been studying mRNA technology for other uses for decades. Researchers are now investigating whether mRNA can be used to create vaccines that protect against other viruses.

A team led by Dr. Paolo Lusso of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) developed and tested an mRNA HIV vaccine in animals. Results of the study were published in Nature Medicine on December 9, 2021.

The experimental HIV vaccine is injected into muscle, where it delivers instructions for making two key HIV proteins, Env and Gag. Muscle cells assemble these two proteins into virus-like particles that are studded with many copies of Env on their surface. These virus-like particles cannot cause infection or disease because they lack the complete genetic code of HIV. Yet they provoke immune responses similar to natural HIV infection.

The researchers first tested the vaccine in mice. They found that, after two injections, it elicited antibodies in all animals that could neutralize HIV. The Env proteins on the virus-like particles produced from the vaccine closely mimicked natural infection. This represents an improvement over previous experimental HIV vaccines. 

They then tested the vaccine in rhesus macaques. Monkeys received a priming vaccine followed by several booster inoculations. By week 58, all vaccinated macaques had developed measurable levels of antibodies that could neutralize many diverse HIV strains. The experimental vaccine also induced other important immune responses, like helper T cells, which aid other immune cells.

The macaques were then exposed weekly to simian-human HIV (SHIV), a form of the virus used for modeling human HIV in monkeys. After 13 weeks of virus inoculations, two out of seven immunized macaques remained uninfected. The other immunized animals had a delay in infection, which occurred after eight weeks, on average. In contrast, unimmunized animals became infected on average after three weeks. Overall, vaccinated monkeys had a 79% lower per-exposure risk of SHIV infection than unvaccinated animals.

The vaccine course was well-tolerated with only mild side effects. These results showed that the novel HIV vaccine was safe and prompted immune responses against an HIV-like virus.”

A study in humans is now in planning phase.

Source: https://www.nih.gov/news-events/nih-research-matters/experimental-mrna-hiv-vaccine-shows-promise-animals

Article: A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques; Peng Zhang, Elisabeth Narayanan, …Paolo Lusso ; Nature Medicine volume 27, pages 2234–2245 (2021)Cite this article

https://www.nature.com/articles/s41591-021-01574-5

Descovy vs. Truvada: tit for tat?

In HIV on November 22, 2019 at 3:38 pm

Current antiretroviral therapy (ART) treatment guidelines and practice have resulted in a pronounced shift from use of tenofovir disoproxil fumarate (TDF – Truvada®) to tenofovir alafenamide (TAF – Descovy®), which is associated with less bone and renal toxicity. Recently, concerns have been raised about increased cholesterol and body weight linked to TAF relative to TDF. In this study, investigators examined changes in cholesterol, body weight, body-mass index (BMI), and American College of Cardiology atherosclerotic cardiovascular disease (ASCVD) risk score in ART-experienced persons living with HIV who switched from TDF to TAF at an academic-based HIV clinic. Before the switch, participants had been on an effective TDF-containing regimen, defined as on TDF >1 year with at least two consecutive HIV RNA levels <200 copies/mL and no levels >200 copies/mL in the previous year.

A total of 110 patients (58% African American; 73% male; mean age, 50; median baseline body weight, 185 pounds; median BMI, 28 kg/m2) met study criteria. During the year after the switch, significant increases were observed in average total cholesterol (by 12.5 mg/dL), LDL cholesterol (by 8.2 mg/dL), HDL cholesterol (by 3 mg/dL), weight (by 3 pounds), BMI (by 0.5 kg/m2), and ASCVD risk score (by 0.4 points). In regression models, switching from TDF to TAF was associated with a 0.45 kg/m2 BMI increase and a 13% increase in ASCVD risk score.

Source: Schafer JJ et al. Changes in body mass index and atherosclerotic disease risk score after switching from tenofovir disoproxil fumarate to tenofovir alafenamide. Open Forum Infect Dis 2019 Oct 4; 6:ofz414. (https://doi.org/10.1093/ofid/ofz414)

Summary appeared in NEJM Journal Watch – 20191120

Comments: This is a retrospective and small study, with caveats – the majority are African American, male, older, high BMI, only one year follow up- yet the results showing a concerning trend and should be verified by larger and more inclusive study- of note, this is from people with HIV infection, and it may or may not apply for those taking Pre-exposure prophylaxis (PreP). BA

HIV Treatment & Weight Gain

In General Health, HIV on November 14, 2019 at 5:44 pm

Following initiation of antiretroviral therapy (ART), many people with HIV gain weight as part of their “return to health.” However, certain antiretroviral medications, including integrase inhibitors, are associated with greater weight gain than others. Now, a manufacturer-sponsored pooled analysis of eight of the sponsor’s trials sheds light on risk factors for this weight gain.

Among 5680 people enrolled in randomized trials of initial ART between 2003 and 2015, median weight increase by week 96 was 2.0 kg. Risk factors for greater weight gain included lower baseline CD4 cell count, higher baseline HIV RNA, black race, and female sex. Participants taking integrase inhibitors (INSTIs) gained more weight than those receiving nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors. Among INSTIs, weight gain was greater with bictegravir and dolutegravir than with elvitegravir/cobicistat (4.24, 4.07, and 2.72 kg, respectively). Among NNRTIs, weight gain was greater with rilpivirine than with efavirenz (3.01 vs. 1.7 kg). Among nucleoside reverse transcriptase inhibitors, weight gain was greater with tenofovir alafenamide than with abacavir, tenofovir disoproxil fumarate, or zidovudine (4.25, 3.08, 2.07, and 0.39 kg, respectively). Extreme weight gain (≥10% increase) occurred in 13% of participants in the first 48 weeks and had risk factors similar to those for weight gain overall.

Appeared in NEJM Journal Watch- edited

Citation: Sax PE et al. Weight gain following initiation of antiretroviral therapy: Risk factors in randomized comparative clinical trials. Clin Infect Dis 2019 Oct 14; [e-pub]. (https://doi.org/10.1093/cid/ciz999)

 

Comments: HIV infection is often associated with weight loss, particularly if left untreated after the initial infection and that has been thought to be through a mechanism that involves TNF-alpha; now with earlier detection and treatment we see less of wasting; however , newer medications have been reported to be associated with undesirable weight gain; treators have remarked on this and discussed it in meetings; this is the first study to look prospectively at this phenomenon.  Specific integrase inhibitors and tenofovir alafenamide were associated with greater increases than other ART drugs. Unfortunately, the two most effective integrase inhibitors are associated with higher weight gain than the less robust one-

New HIV Strain

In HIV on November 8, 2019 at 4:58 pm

Researchers have found a new strain of HIV in humans. Here is an edited clip from that paper:

<<The origins of the human immunodeficiency virus (HIV) pandemic have been traced to the Democratic Republic of Congo (DRC), where estimates place the emergence of HIV in the 1920s.  Consistent with an early expansion of HIV in this region, strains from DRC exhibit broad genetic diversity and include all of the recognized subtypes, many circulating recombinant forms (CRFs) [recombinant = genetic material produced when segments of DNA from different sources are joined to produce recombinant DNA] , and an abundance of unique recombinant forms (URFs) and unclassifiable sequences. Current HIV nomenclature [choosing of names for things] guidelines specify that complete genome sequences from at least three non-transmission linked cases are required to establish a new subtype or CRF classification for HIV.>>

This paper in JAIDS had done just that. So now we officially have subtype L.

Source: Complete genome sequence of CG-0018a-01 establishes HIV-1 subtype;  LYamaguchi, Julie BS1; McArthur, Carole MD2; Vallari, Ana MS1; Sthreshley, Larry PhD3; Cloherty, Gavin A. PhD1; Berg, Michael G. PhD1; Rodgers, Mary A. PhD1- JAIDS Journal of Acquired Immune Deficiency Syndromes: November 06, 2019 – Volume Publish Ahead of Print – Issue – doi: 10.1097/QAI.0000000000002246

Free Access to JAIDS article

Appeared in NEJM journal watch November 8, 2019

Comments: As important as this discovery might be from scientific view point, it probably has no impact clinically – BA

 

Virus load is undetectable, but active virus still?

In HIV, Immune System on August 23, 2016 at 4:16 pm

HIV-infected patients taking antiretroviral medications with undetectable viral loads continue to have detectable HIV DNA in CD 4+ cells despite many years of therapy. Previous studies have found that most of that HIV DNA is defective and unable to replicate, a veritable “defective” of proviruses (the genetic material of a virus as incorporated into, and able to replicate with, the genome of a host cell). The current consensus view of the “defective” proviruses is that these are dead-end products that do not give rise to progeny (offspring) virus and thus collectively represent a “graveyard” of viruses.Now, a careful analysis reveals that these defective proviruses may not quite be as “dead” as we thought.

Investigators have now studied HIV DNA proviruses from four patients with undetectable plasma viral loads. As expected, the patients had defective proviruses with deletions or lethal mutations. Surprisingly, when cytoplasmic RNA from these patients was sequenced, the investigators found novel RNA transcripts matching the defective proviruses. These transcripts appeared to be capable of producing viral proteins. Investigators  propose that the proviruses persistently present in combination antiretroviral therapy-treated patients are not defective in a conventional sense, but rather represent incomplete forms of proviruses encoding translationally competent HIV-RNA transcripts. Strategies directed toward curing HIV-1 infection and eliminating the state of persistent immune activation need to include approaches designed to eliminate cells harboring such proviruses.

 

Appeared in JWatch August 5, 2016

Citation(s):Imamichi H et al. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc Natl Acad Sci U S A 2016 Aug 2; 113:8783. (http://dx.doi.org/10.1073/pnas.1609057113)

 

Comments: this could explain the presence of viral activation ( seen by careful analysis of T-cell panel, mediators, ..etc) in those with undetectable plasma virus load. The question remains, should this be controlled, can it lead to an increase in CD4+ counts in those with undetectable virus load? This is probably one of the biggest clinical hurdles left_BA

 


It is not always the medicine.

In HIV on September 24, 2013 at 6:38 pm

When patients fail (high virus load) their initial (first line) antiretroviral therapy, we are often confronted with the question: was the failure due to poor choice of medication (weak combo? did we miss a mutation although the resistance testing shows no resistance?) or was it because the patient did not take the medications as often as they were prescribed?

In a retrospective cohort analysis conducted in South Africa, investigators used stored specimens from patients with treatment failure on first-line ART to determine the contributions of resistance and nonadherence to failure or success with second-line regimens. From among 417 patients switching to second-line ART with viral loads >400 copies/mL, 122 had samples for genotyping, drug-concentration measurement, or both (73 had both, 42 had genotyping only, and 7 had drug-concentration measurements only). Overall, 83 of the 122 (68%) achieved viral suppression on second-line ART. Patients with ≥1 nucleoside reverse transcriptase inhibitor drug-resistance mutation (DRM) before switching regimens were more likely to achieve viral suppression than those with no DRMs. Moreover, patients with subtherapeutic first-line ART drug concentrations who had no major DRMs were less likely to achieve suppression than those with major DRMs or those with therapeutic first-line drug concentrations. Overall, patients with subtherapeutic first-line ART and no major DRMs were the least likely to achieve viral suppression with second-line ART, followed by those with subtherapeutic first-line ART and major DRMs, and, finally, those on therapeutic first-line ART.

Citation(s):Johnston V et al. Viral suppression following switch to second-line antiretroviral therapy: Associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch. J Infect Dis 2013 Sep 13;

Appeared in NEJM Journal watch on 9/23/2013.

Comment: Although this is a retrospective study, it points to adherence, or lack of it, as the main cause for failure of first regimen; it also predicts the success of the second regimen!  Medicine in bottles do not work_BA

MERSA

In General Health, HIV, Immune System on February 28, 2013 at 6:55 pm

Earlier studies have suggested that HIV-infected individuals have an increased prevalence of nasal colonization with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and a greatly increased risk for CA-MRSA skin and soft-tissue infections. To explore the prevalence and colonization burden of CA-MRSA in HIV-infected and HIV-uninfected individuals, researchers studied patients admitted to a general medicine or HIV ward service at a Chicago hospital between March 2011 and April 2012.Patients were enrolled within 72 hours after admission and were swabbed for CA-MRSA at sites typical for colonization. Risk factors for CA-MRSA colonization were determined using a targeted questionnaire and review of medical records. Of the 745 participants (64% men; 63% black; mean age, 48), 374 were HIV infected. The overall prevalence of CA-MRSA colonization was 10% at the nares and 15% at extranasal sites. HIV-infected patients had a higher prevalence of colonization at any site than did HIV-uninfected patients (20% vs. 11%; P=0.002). Extranasal colonization was most frequent in perirectal and inguinal sites for HIV-infected patients, and in perirectal, inguinal, and throat sites for HIV-uninfected patients. In HIV-infected patients, mean CD4-cell count and median viral load did not differ between those who were and were not colonized with CA-MRSA. In multivariate analysis, factors associated with an increased colonization burden (number of sites colonized per patient) in HIV-infected patients were current or recent incarceration, male sex, and younger age; Hispanic ethnicity was associated with a decreased colonization burden. In HIV-uninfected patients, temporary housing was the only factor associated with a higher CA-MRSA colonization burden. Most of the CA-MRSA isolates (74%) were USA300. Predictors of this strain included HIV infection, male sex, younger age, and current or former illicit drug use.

Published in Journal Watch HIV/AIDS Clinical Care

Citation: Popovich KJ et al. Community-associated methicillin-resistant Staphylococcus aureus colonization burden in HIV-infected patients. Clin Infect Dis 2013 Feb 12;

Comments: The data is not new, but still important to emphasize: one out five HIV infected individuals carry MRSA and not in the usual places (so cultured the nasal area may not be revealing). This has diagnostic and treatment implication as well as public health change in policies_ BA

 

Deadlier than HIV?

In General Health, HIV on February 25, 2013 at 7:11 am

Smoking is extremely common among HIV-infected patients. To quantify the contribution of smoking to mortality in HIV patients, researchers analyzed a median of 4 years of follow-up data from 2921 patients (78% men, 77% on antiretroviral therapy at baseline) in a Danish national HIV cohort and from 10,642 matched controls in the Danish general population. Each patient’s smoking status — current (any weekly tobacco use), previous, or never — was assessed at time of enrollment and held constant for purposes of analysis. Duration of smoking was not considered. Outcomes data came from Danish national registries. In the HIV-infected cohort, analyses adjusted for HIV-related and other clinical variables revealed that all-cause mortality was more than fourfold higher, and non–AIDS-related mortality was more than fivefold higher, among current smokers than among never smokers. The population-attributable risk for death related to smoking was about 62% in the HIV cohort and 34% in the control group. Compared with controls, HIV patients had roughly triple the excess mortality and life-years lost from smoking. The relative risk for death associated with smoking did not differ significantly between the two groups.

Comment: Striking numbers: 12.3 life-years lost from smoking, compared with 5.1 lost from HIV infection!

CITATION: Helleberg M et al. Mortality attributable to smoking among HIV-1–infected individuals: A nationwide, population-based cohort study. Clin Infect Dis 2012 Dec 18.

Published in Journal Watch HIV/AIDS Clinical Care.

KP-1461: A Novel Approach in treating HIV infection

In HIV on February 25, 2013 at 6:38 am

Most of the antiretrovirals in development represent additions to the currently available drug classes. KP-1461 belongs to a novel class of drugs — viral decay accelerators — that increase the mutation rate, with the goal of exceeding the virus’s error threshold and thereby decreasing replication. In a recent manufacturer-sponsored, phase IIa study, researchers evaluated the safety, tolerability, and efficacy of 4 months of oral KP-1461 (1600 mg twice daily).The study involved 24 HIV-infected patients who had not received antiretroviral therapy (ART) for 16 weeks (83% men; median age, 47.5; mean duration of HIV infection, 15 years; median baseline CD4 count, 429 cells/mm3; median viral load, 68,450 copies/mL). All had received nonsuppressive ART in the past or had documented HIV resistance to multiple ART classes, or both, and many had intolerance to available agents. Trough levels of KP-1461 during the study exceeded those previously shown in vitro to be associated with significant viral load declines. Twelve patients experienced possibly drug-related adverse events, most of them mild to moderate in severity. Two patients discontinued medications because of adverse events, and two died of causes unrelated to study medications. No significant effect on viral load, CD4-cell count, or drug-resistance pattern was seen among the 13 patients who completed 4 months of treatment. Comparison of viral sequences between 10 of these patients and controls revealed mutation-pattern changes consistent with the drug’s proposed mechanism of action.

Comment:These are small and early data; however, and despite some shortfalls (the choice of patients (not totally naive, and not typical experienced patients), unusual disposition of some of the study participants), these data should lead to larger studies to assess the true role of this treatment.

CITATION: Hicks C et al. Safety, tolerability, and efficacy of KP-1461 as monotherapy for 124 days in antiretroviral-experienced, HIV type-1 infected subjects. AIDS Res Hum Retroviruses 2013 Feb; 29:250.

Published in Journal Watch HIV/AIDS Clinical Care

Lersivirine: unfinished story

In HIV on February 25, 2013 at 6:28 am

Lersivirine — a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) from the class of efavirenz (Sustiva®) nevirapine (Viramune®), rilpivirine (Edurant®)and etravirine (Intelence®)— has shown promise in early clinical trials, but its comparative efficacy has not been established. In a manufacturer-sponsored, placebo-controlled, double-blind, phase IIb, dose-seeking study, 195 HIV-infected adults with viral loads 1000 copies/mL and CD4 counts 200 cells/mm3 were randomized to receive tenofovir/FTC plus either lersivirine (500 or 750 mg once daily) or efavirenz (600 mg once daily). In a modified intent-to-treat analysis, the proportion of patients with viral loads <50 copies/mL at week 48 was 78.5% in both lersivirine arms and 85.7% in the efavirenz group. Virologic failure was somewhat more common with lersivirine, but efavirenz had a slightly higher adverse-event rate.

Comment: Lersivirine is a novel NNRTI with a unique resistance pattern, broad cross-clade activity, and a promising adverse-event profile. Although the current study was not adequately powered to assess noninferiority to efavirenz, the results in all three arms were similar enough to justify large-scale, appropriately powered studies of lersivirine. Unfortunately, the makers of the drug have decided not to pursue further development, so trials to determine the drug’s true safety and efficacy will not take place.

CITATION: Vernazza P et al. Efficacy and safety of lersivirine (UK-453,061) versus efavirenz in antiretroviral treatment–naive HIV-1–infected patients: Week 48 primary analysis results from an ongoing, multicenter, randomized, double-blind, phase IIb trial. J Acquir Immune Defic Syndr 2013 Feb 1; 62:171.

Published in Journal Watch HIV/AIDS Clinical Care