Dr Rohan Bopage

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

Rohan Bopage

Rohan Bopage

Rohan is a consultant physician with dual specialist qualifications in infectious diseases (FRACP) and sexual health medicine (FAChSHM) and works at The Albion Centre in Sydney. He is a conjoint lecturer at the School of Public Health and Community Medicine at University of NSW.  His main clinical and research interests are: HIV, STIs & viral hepatitis care in marginalised populations; HIV/STIs and recreational drug use; bio-medical prevention of HIV
CROI 2016: Intensive cervical cancer screening only needed in HIV positive women with low CD4

Intensive cervical cancer screening may be appropriate for HIV-positive women with a CD4 count below 500 and for immunosuppressed solid organ transplant recipients--but not for HIV-positive women with more CD4s or for women on immunosuppressive therapy [1]. Those conclusions arose from a 121,000-woman case-control study in the Kaiser Permanente healthcare system in northern California. Women with HIV had twice higher odds of advanced cervical intraepithelial neoplasia (CIN) or cervical cancer than women without HIV.

 

Kaiser investigators conducted this study to get a better fix on which HIV-positive and other immunosuppressed women need intensive cervical cancer screening. The researchers considered all women 18 to 70 years old in care between July 1996 and June 2014. Cases were women with incident (newly diagnosed) CIN 2, CIN3, or cervical cancer, designated CIN2+ or CIN3+. For every case the researchers identified 5 women without CIN2+ matched by age, diagnosis date of the case, years in the Kaiser system, and date of first Kaiser Pap test. They analyzed risk of CIN2+, CIN3+, and cancer in (1) all HIV-positive (versus negative) women, (2) HIV-positive (versus negative) women grouped by recent CD4 count below 200, 200 to 499, and 500 or higher, and (3) women with non-HIV immunosuppression, including immunosuppressive therapy (such as calcineurin inhibitors and corticosteroids) in the last 18 months (versus no therapy) and solid-organ transplant (versus no transplant).

Cases were 20,146 women with CIN2+, including 11,275 with CIN3+ and 646 with cervical cancer. Because of matching, cases and controls had the same average age (36) and similar numbers of years in the Kaiser system (6.4 and 6.6 years). Cases and controls were also similar in proportions of whites (54% and 49%), Hispanics (20% and 21%), and blacks (8% and 9%). Cases included a higher proportion of smokers (19% versus 13%). About 2% in each group had been vaccinated against HPV.

Cases included 36 women with HIV (0.18% of 20,146) and controls included 79 HIV-positive women (0.08% of 100,780). All of this percentage difference lay among women with a CD4 count below 500. The proportion of HIV-positive cases with a recent CD4 count above 500 was 0.04%, exactly the same proportion of HIV-positive controls with a recent CD4 count above 500. Numbers of cases and controls with recent immunosuppressive therapy were 1370 (6.8% of cases) and 6429 (6.4% of controls). Cases included 51 transplant recipients (0.25% of cases) and controls included 69 transplant recipients (0.07% of controls). 

In adjusted analyses, compared with HIV-negative women, HIV-positive women had 2.0-fold higher odds of CIN2+ and 2.3-fold higher odds of CIN3+. HIV-positive women with a recent CD4 count under 200 CD4s had 5.7-fold higher odds of CIN2+ and women with 200 to 499 CD4s had 3.0-fold higher odds. But risk of CIN2+ was not greater in HIV-positive women with 500 or more CD4s compared with HIV-negative women. The same held true for the CIN3+ analysis: Odds were 5.4-fold higher with a recent CD4 count under 200 CD4s and 3.6-fold higher with 200 to 499 CD4s, but risk was no greater in women with 500 or more CD4s.

Women with a solid-organ transplant had independently higher odds of CIN2+ (3.3-fold) and CIN3+ (2.9-fold). But women on immunosuppressive therapy did not have higher odds of CIN2+ or CIN3+. 

Among the 646 women in whom cancer developed, 2 (0.3%) had HIV compared with 0 of 3230 matched controls; 34 of 646 women with cancer (5.3%) had recent immunosuppressive therapy compared with 156 of the 3230 matched controls (4.8%); and no woman with cancer had a solid-organ transplant compared with 4 matched controls (0.1%). 

The Kaiser team concluded that HIV-positive women had 2-fold higher odds of CIN2+ and CIN3+, but these higher odds applied only to women with a recent CD4 count below 500. Solid-organ transplantation conferred 3-fold higher odds of CIN2+ and CIN3+, but recent immunosuppressive therapy did not affect CIN2+ risk. 

Take home message: more frequent cervical cancer screening may be needed only for subsets of women with HIV and non-HIV immunosuppression, including HIV-positive women with a CD4 count below 500 and solid-organ transplant recipients. They suggested that future studies addressing these issues "should take into account harms and costs anticipated with various screening strategies."

Reference

 

1. Silverberg MJ, Leyden W, Steven Gregorich S, et al. Is intensive cervical cancer screening justified in immunosuppressed women? Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 162.

Tagged in: CROI2016
CROI 2016 : Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss : Proof of concept study

HIV infection is an independent risk factor for osteoporosis. Initiation of ART induces additional 1-6% loss in bone mineral density (BMD). ART-associated bone loss occurs early and happens with most of ART agents.

Zoledronic acid is a biphosphonate drug licensed for the treatment of bone-related cancers alongside chemotherapy and for the treatment of osteoporosis in men and women at increased risk of fracture. It is administered as an infusion once a year. The drug slows down the loss of calcium from the bones, reducing the risk of fractures.

Reduced bone mineral density is common in people living with HIV, and as previously noted, modest bone mineral loss is a common occurrence during the first year of antiretroviral therapy. Investigators from Emory University School of Medicine, Atlanta, designed a study to investigate whether a single infusion of zoledronic acid could limit bone mineral loss during the first year of antiretroviral therapy.

This was a single-centre, randomised, double-blind, placebo controlled phase 2 study. Patients starting HIV therapy for the first time with no history of bone loss were eligible for inclusion. All participants received an antiretroviral regime of atazanavir with tenofovir/emtricitabine. Patients were randomised to receive a single 5mg infusion of zoledronic acid or placebo. The study lasted 48 weeks with assessment of bone turnover and bone mineral density at baseline and weeks 12, 24 and 48.

Therapy with zoledronic acid was associated with a 74% reduction in bone loss by week 12. The benefits persisted through to week 24 and 48 (65% and 56% reduction, respectively, relative to placebo).

By week 12, patients in the treatment arm had an 8% increase in lumbar spine bone mineral density relative to placebo, the difference increasing to 11% at weeks 24 and 48. At week 48, lumbar spine bone mineral density had increased by 2% in patients treated with zoledronic acid; this compared to a 4% decrease among patients who received the placebo. Lumbar spine T- and Z-scores were significantly higher among patients who received zoledronic acid versus placebo at all follow-up points (all p < 0.05). Similar trends were also observed at the hip and femoral neck.

Zoledronic acid was well tolerated with no major adverse events reported. Rates of viral suppression and CD4 cell increase were similar between the treatment and placebo arms.

The investigators conclude that a single infusion of zoledronic acid at the time HIV therapy was started prevented antiretroviral-induced bone resorption and bone loss at key fracture-prone body sites. The benefits of therapy were present at week 12 and persisted through 48-weeks of follow-up. The researchers suggest that zoledronic acid could be used as a prophylaxis against bone mineral loss during the first year of antiretroviral treatment and call for a multicentre randomised trial to confirm their findings.

Take home message: Single dose of zoledronic acid infusion may be an effective preventative measure of BMD loss in HIV

Tagged in: CROI2016

Five of 404 men who have sex with men (MSM) or transgender women taking a maraviroc-containing preexposure prophylaxis (PrEP) regimen or tenofovir/emtricitabine (TDF/FTC) picked up HIV infection in the 48-week HPTN 069/ACTG A5305 trial [1]. All infected men had no, low, or variable drug levels at HIV seroconversion. But results of a substudy suggested maraviroc alone may be less potent than maraviroc/TDF or maraviroc/FTC [2]. 
 
Maraviroc is a reasonable PrEP candidate because it concentrates in the genital tract and rectum and can be taken once daily. To explore maraviroc's potential as PrEP alone or with TDF or FTC, HPTN and ACTG collaborators recruited HIV-negative men or transgender women who did not inject drugs and who had condom-free anal sex with one or more HIV-positive or serostatus-unknown men in the past 90 days. The researchers randomized them to 48 weeks of maraviroc alone, maraviroc/FTC, maraviroc/TDF, or TDF/FTC, all once daily. Thus each man took 3 pills daily (including matching placebo).
 
The trial enrolled 406 people, all male at birth and 7 (2%) transgender women. Median age stood at 30 years and ranged from 18 to 70. Of the 406 people randomized, 404 started study drugs and 340 (84%) completed the study. Thirty-seven participants (9%) stopped study drugs early, with no differences by study arm. Time to permanent drug discontinuation did not differ between arms. Analysis of 18 men per study arm showed that TDF or FTC did not affect maraviroc concentrations. In a random subset of 160 participants, all drugs could be detected in 83% of participants at week 24 and 77% at week 48, with no difference between arms.
 
Ninety men (22%) had 115 sexually transmitted infections diagnosed during follow-up, a finding indicating a high rate of continuing sex. Five men became infected during follow-up for an annual incidence of 1.4% (95% confidence interval 0.8% to 2.3%). Four were taking maraviroc alone and one was taking maraviroc/TDF.(The study was not powered to evaluate efficacy.)
 
At HIV seroconversion, the man taking maraviroc/TDF had undetectable levels of both drugs. One man on maraviroc alone had no detectable maraviroc at seroconversion, while the other three had levels of 0.7, 6.7, and 145 ng/mL. The expected predose maraviroc level is 32 ng/mL, so only one man had good maraviroc levels at seroconversion. But in all 3 men with detectable maraviroc at seroconversion, levels were highly variable throughout the study, indicating off-and-on PrEP use. All 5 men got infected with virus using the R5 receptor (which maraviroc blocks) and none had genotypic resistance to maraviroc.
 
The HPTN/ACTG team proposed that "maraviroc-containing regimens should be considered for testing in clinical efficacy trials." Whether to go ahead with solo maraviroc or maraviroc plus TDF remains an open question. A substudy in which researchers tested the four regimens in colorectal tissue explants of 55 study participants found significantly less viral suppression with maraviroc alone than with the three combination regimens [2]. But the HPTN/ACTG team noted that they have yet to correlate those results with pharmacokinetic adherence data. Also, the same regimens are being tested in women, so decisions on future trials must await those results.

Take home message: Maraviroc is a promising alternative oral HIV PrEP agent but research is still at very early stages.


References
1. Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 103

2. McGowan I, Nikiforov A, Young A, et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 104. 

Tagged in: CROI2016
Recovery of Bone Mineral Density After Stopping Oral HIV PrEP

The slight loss in bone mineral density associated with HIV PrEP antiretroviral use is reversible in young adult patients who stop taking the drugs, according to findings presented by Robert Grant today at the CROI in Boston.

 
The findings result from a bone mineral density substudy of two large clinical trials, iPrEx and iPrEx OLE.Data from the substudy presented today illustrate that bone mineral density decreased a measurable but clinically insignificant amount over the course of a year in young adult males and transgender participants with an average age of 24 taking a protective amount of PrEP. However, six months after stopping the regimen, bone mineral density levels in the spines of these individuals increased to levels consistent with study participants of the same age who took a placebo. Hip bone mineral densities also increased in the first six months after stopping PrEP and returned to normal levels by a median follow-up time of 73 weeks.
 

Previous studies using sensitive scans have shown that HIV medications containing tenofovir slightly reduce bone mineral density, though not to a degree at which patients experience complications. This is the first study to show that this effect is reversible when a patient can stop PrEP, such as when an individual enters into a mutually monogamous relationship with another HIV-negative individual. 
 

Take home message: It appears that Truvada-based oral PrEP may not pose an irreversible effect on bone mineral density in young adults.

Tagged in: CROI2016
CROI 2016 Case-based workshop on HCV

I found the case-based workshop on HCV quite useful. The session highlighted some of the difficult therapeutic scenarios with current DAAs. It also mentioned some of the limitations of current DAAs and research gaps in this area.

Here I have summarised important points relevant to HIV & HCV prescribers. Standard abbreviations are used.

HIV and HCV co-infection

Even though efficacy of current DAAs in HIV/HCV high and generally equivalent to HCV mono-infections, this is still a "special" population with therapeutic challenges

DDI with HIV ART

LDV/SOF with TDF increases tenofovir plasma concentrations; greater effect when combined with RTV boosted PIs. Avoid LDV/SOF if CrCl< 60 or with TDF+ RTV-boosted PI

However, the clinical significance of elevated TDF level here is not very clear at this stage. But when LDV/SOF and TDF given, frequent monitoring recommended eg week 2 & 4 renal functions monitoring

What about TAF and LDV/SOF? Data was presented for E/C/F/TAF and R/F/TAF. Tenofovir concentration are increased but well below the concentrations with TDF.

Take home message: LDV/SOF and TDF:  Be aware contra-indications and frequent renal function monitoring while on DAAs

DDI with other meds

One important DDI highlighted in the case was PPIs and SOF/LDV. Chronic PPI therapy is not uncommon in PLHIV and in many cases, it is unnecessary. There is significant decrease of LDV concentrations with PPIs. The data from HCV TARGET study sub-analysis was presented. SVR 12 with SOF/LDV was reduced from 90% to 70% when PPIs are used as baseline.

Take home message:  PPIs can significantly compromised SOF/LDV efficacy. This is good opportunity to review patients on long term PPIs and cease if not absolutely necessary. One more reason to stop unnecessary long term PPIs

Can we stop HIV treatment temporarily when there are significant DDIs with HIV ART and HCV DAAs? Panel members felt with the available of new HIV ARTs, stopping HIV treatment temporarily is not acceptable and it’s recommenced to change HIV ART to a suitable regimen prior to HCV DAA treatment.

Shorter course of DAAs

In some subpopulations, SOF/LDV and SOF/DCV 8 weeks has high efficacy comparable to 12 weeks treatment.

For an example, In GT1, treatment naive, non-cirrhotic and baseline HCV VL less than 6 million IU/mL treatment can be shorted to 8 weeks of SOF/LDV.

However, data is currently not available for HIV/HCV co-infections. The panel members recommendation was until we have more data for co-infections, avoid 8 weeks treatment.

Take home message: Avoid shorter course (less than 12 week ) of SOF/LDV or SOF/DV in HIV/HCV co-infections until more clinical data available.

 

Tagged in: CROI2016

RT @hepqld: Curing #hepatitis C is easy, and no longer needs a specialist to prescribe treatment. Community doctors play a pivotal role in…

ASHM ASHM