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CROI 2013 Report
Nelson Vergel
I was happy to attend
CROI-2013 in Atlanta on March 3-6, 2013. These are areas of great interest to me and
in no way attempts to summarize the main findings reported at the conference.
For abstract information, refer to http://www.retroconference.org/AbstractSearch/default2.aspx?conf=22
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A baby girl gets cured
The most popular media story of the conference on retrovirus and opportunistic infections that took place in Atlanta was the story of a baby that was cured of HIV infection. The baby was born in Mississippi from a street drugs using mother that didn't have HIV care during pregnancy. The hospital where she went to give birth did not have HIV medications to give her prior to birth to prevent HIV transmission to the baby. Immediately after birth two different viral loads were obtained and the baby was started on triple antiretroviral therapy. The baby had an HIV viral load in the 20,000 copies/ml range, and rapidly became undetectable after her doctor managed to get HIV treatment for her within 3 days. The baby continued the treatment for at least 18 months, then her mother and baby were lost to follow up and decided to discontinue their HIV treatment on her own. A few months later, when they were found and the baby returned to care, the HIV viral load remained negative and there was no evidence of ongoing replication or infection with HIV. The baby has been followed for several months off therapy without evidence of the virus returning. This aggressive treatment probably worked because the baby was very recently infected, and did not have a chance to establish a significant reservoir, and because of that the antiretroviral treatment was capable of clearing the infection. The amount of memory T cells in a newborn is very small, and those cells constitute the best characterized HIV reservoir. This case shows that if we could prevent reservoir formation by using anti-retrovirals alone we may be able to eliminate the virus. New studies will aggressively treat newborns within a few hours of birth with triple antiretroviral therapy immediately after birth, and if infection is confirmed maintain this treatment for at least a year, and then discontinue it and see how many children can be cured with that strategy. These studies will have to be done in Africa because in the United States there are not enough positive infected children since most infections are prevented by giving antiretrovirals to HIV+ pregnant women. This fortunate case may have a dramatic impact on eliminating HIV from newborns all over the world. It will be our first massive cure initiative! Neurocognitive impairment HIV+ aging patients may present mild cognitive impairment even after long term successful HIV treatment. There is a lot of controversy about whether or not using HIV antiretrovirals that penetrate the central nervous system (CNS) better may make a difference.
Dr. Letendre of San Diego created a system that scored HIV drugs
according to their penetration in the CNS. He hypothesized that treatments with better CNS penetration scores
would be better in preventing the development of neurocognitive impairment.
Two studies were presented at CROI that looked into this hypothesis in different ways. In the first study, presented by Ron Ellis, individuals that were starting a new antiretroviral regimen were randomized to a regimen with good CNS penetration and compared to patients that were randomized to a not CNS targeted regimen. The study was a small and with slow accrual. The selection of CNS targeted regimen did not make a difference at 16 weeks, either in sophisticated neurocognitive testing or in biological markers in the cerebral spinal fluid (CFS). In fact 87% of the patients randomized to a “non-CNS targeted” regimen reached virological suppression in the CSF, versus 68% of those receiving a CNS targeted regimen. Since the study only lasted 16 weeks no one knows if an effect would be seen in the longer term.
We are seeing more evidence that it is probably not a
requirement that an antiretroviral drug has to penetrate the CSF to be able
to exert a beneficial effect in brain function. Also, some of the better CNS
penetrating drugs like efavirenz may also have CNS related side effects that
may mask the potential benefit provided by its better penetration.
Another study called PICASSO evaluated the cognitive function of patients
were on monotherapy of boosted darunavir (Prezista) or Kaletra versus a combination of two nucleoside analogues
with these boosted protease inhibitors. Darunavir/ritonavir and Kaletra do
not have CNS penetration, so the hypothesis was that those patients taking
those drugs as monotherapy should have some neurocognitive deterioration as a
consequence. However, this was not the case which is yet another punch to the
theory that CNS penetration can prevent or improve cognitive problems.
Another study showed that mega HAART (more than 3 HIV
medications in combination) did not
improve the neuropsychological performance compared to stand on
antiretroviral therapy in patients recently infected with HIV infection.
I think these studies have all failed to monitor patients’
quality of life of the different regimens to see any association on sleep
quality, fatigue, gut issues, etc on cognitive function beyond the effect of
CNS penetrating antiretrovirals.
New HIV Medications |
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Several studies were presented on new HIV medications:
1. Dolutegravir. This new once a day unboosted integrase inhibitor has been proven to reduce HIV viral load rapidly and effective when compared to current standard of care. It also seems to present the same lack of interactions as raltegravir. The pharmacologic properties of dolutegravir were the topic of several presentations. Poster 178LB investigated concentrations in the CSF, and found that CSF concentrations were the same as blood concentrations in HIV+ naïve patients. The dolutegravir+ abacavir+3TC achieved an impressive -3 log CSF viral load reduction at 16 weeks similar to that in plasma. This combination is currently being formulated as a one-pill once a day regimen.Poster 531 assessed drug concentrations in colorectal tissue, as well as in male and female reproductive tracts. Low drug concentrations were observed in reproductive tract secretions of both men and women. Interestingly, however, tissue concentrations in female reproductive tract and rectum in the same people were adequate. It is important to note that integrase inhibitors as a class seem to penetrate reservoirs a lot better than other drug classes (NNRTIs are almost as effective in doing so).
2. Merk’s new once a day non-nucleoside MK-1439. Poster 527 assessed the PK of this drug on HIV- people. The PK profile of the drug is conducive to daily dosing. A drug interaction study with midazolam showed that MK-1439 was not an inducer or inhibitor of CYP3A. Other studies are being performed to asses any potential drug interactions. Presentation 100 described a monotherapy study comparing both 25mg and 200mg daily doses of MK-1439 with placebo for 1 week in HIV-infected individuals. During these 7 days, no serious adverse effects judged to be associated with MK-1439 were observed. Adequate viral load reductions in the range of -1.26-1.37 logs were attained in 7 days. We await further studies on this non-nucleoside that may present a new resistance profile that may possibly help treat HIV with several non-nucleoside resistance mutations. I hope it does has the same lipid profile as others NNRTIs without the rash and CNS issues.
3. Cenicriviroc. Week 24 analysis of cenicriviroc (CVC) was presented in abstract 106LB. CVC is an entry inhibitor given once daily CCR5 and CCR2 antagonist. Two different doses of CVC (100 mg and 200 mg once daily) were compared with efavirenz, both in combination with Truvada in treatment-naïve adults. The percentages of individuals experiencing virologic success were similar between the CVC and EFV groups. However, virologic non-response was higher with CVC than with EFV. It seemed to be better tolerated than efavirenz. We will see if the inhibition of the CCR2 receptor will translate into reduced inflammatory markers when compared to Atripla. The best dose is yet to be selected for phase 3 studies.
4. Tenofovir pro-drug - tenofovir alafenamide fumarate (TAF).Formerly known as GS-7340. This prodrug promises similar efficacy than tenofovir but fewer kidney issues. Posters 529 and 540 examined the effects of TAF on the kidneys. Unlike tenofovir (TDF), TAF does not concentrate in the kidneys. Patients with renal impairment receiving TAF had less than 2-fold increases in peak blood level concentration and drug exposure, which is not considered clinically relevant (TDF presents a problem in these patients). These findings suggest TAF may be able to be used in individuals with renal dysfunction without needing to reduce the dose as currently done with TDF.
Presentation 99LB described a phase 2 trial comparing elvitegravir+cobicistat+ emtriva with TDF or with TAF. At week 24, the TAF-containing regimen had similar efficacy, and an improved side effect profile than Stribld. The group receiving TAF experienced no renal side effects, and a significantly smaller decline in bone density. I am looking forward to more data!
5. Long acting formulations. Previous data have been presented with long acting formulations of a monthly intramuscular (IM) injection of rilpivirine and injectable formulations of the integrase inhibitor GSK744 (a second generation integrase inhibitor, both IM and sub-cutaneous) where therapeutic drug levels are sustained for well over a month. Another drug that has been studied for a few years is the monoclonal antibody ibalizumab as a CD4 receptor entry inhibitor to overcome drug resistant HIV is based on intravenous delivery every 2-4 weeks.
Oral abstract 24LB presented data on a long acting nano-formulation of GSK744. The drug was administered via a single intramuscular injection to HIV- vounteers and found to have a half-life of 21 to 50 days, which may allow a once monthly or even once quarterly dosing schedule. To assess the efficacy of this long acting GSK744 formulation for PrEP, 8 macaques received intramuscular doses of GSK744 at two time points 4 weeks apart. All eight of the control macaques receiving placebo became infected with SHIV. None of the 8 treated macaques had detectable virus 3 weeks after the final viral challenge.
Long acting regimens including one or more injections of three compounds monthly may require oral lead in periods to assess tolerability and easy withdrawal in case of side effects Also, careful guidelines for treatment discontinuation will be important if the three compounds have different half lives.
Dr Puliguji from University of Nebraska presented results on a nanoformulation of atazanavir/ritonavir that in a mouse study which resulted in ten-fold higher concentrations in plasma and tissue and sustained for two weeks following a single intramuscular injection. It will be interesting to see studies on nanoformulations of darunavir and other popular HIV antiretrovirals in the future.
In my opinion, this is one of the most exciting areas of HIV drug development in the present that may change the paradigm with improved adherence, great pre exposure and post exposure protection, and hopefully side effect profile.
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