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Antiretroviral Therapy at
IAS Conference on Pathogenesis, Treatment and Prevention
Vancouver, BC, Canada, July 19-22, 2015
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David H Shepp, MD
Associate Professor of Medicine
Hofstra-North Shore LIJ School of Medicine
When to START. IAS 2105 was the venue for the first presentation of the much-anticipated results of the START study [1], also simultaneously published in the NEJM [2]. Nearly 4700 HIV-infected participants with a CD4 count >500 were randomized to immediate ART or deferral of ART until CD4 declined to <350 or the occurrence of a primary endpoint event, the composite of an AIDS-defining event, a serious non-AIDS illness (cardiovascular disease [CVD], ESRD, hepatic decompensation or non-AIDS cancer) or death. More than half were from low or middle income countries. The data safety monitoring board recommended termination of the study after a mean follow-up of 3 years because of a 57% reduction in primary end-point events in the immediate ART arm (1.8%) vs. the deferred ART arm (4.1%), yielding a hazard ratio of 0.43 (95% CI: 0.30-0.62, p<0.001). When considered separately, AIDS events were reduced by 72% (p<0.001) and non-AIDS events by 39% (p=0.04). The AIDS events result was largely due to differences in tuberculosis and AIDS-related cancers, while the non-AIDS result was largely due to differences in non-AIDS cancers. The reduction in all cancers was 64% (p=0.001). Neither mortality nor CVD events were significantly reduced, and hepatic and renal events were rare. The benefit of immediate ART was apparent when analyzed by gender, race, age, baseline CD4 and by country income level. Serious clinical adverse events not included in the primary end-point were not increased by immediate ART and bacterial infections were significantly reduced. Very few primary end-point events occurred when the CD4 was <350 and most occurred when CD4 was >500, indicating the study result was not driven by failure to initiate ART according to protocol or by those non-adherent to ART. This finding also shows that CD4 is an incomplete gauge of HIV-related immune deficiency.
There could still be some objections to the results of START. If it had been conducted entirely in high-income countries with a low risk of tuberculosis, the differences between arms may have been smaller. However, other benefits such as reduction in CVD may have emerged. Immediate ART did not significantly reduce cardiovascular disease or mortality. This may have been due to low numbers of events. Only 26 CVD events were observed, perhaps reflecting the relatively low overall risk of the study population, the known association of CVD risk with low nadir CD4, prevented by the study design, and the benefits of being in care conferred by study participation. Mortality was also low, but a non-significant trend favored the immediate ART arm (12 vs. 21 deaths, p=0.13).
The START study provides high level evidence supporting the concept that untreated HIV infection is bad for health and given the availability of safe and effective ART, all infected individuals should be treated. The results come as no surprise because a strong line of evidence from a series of sophisticated cohort studies have previously pointed in this direction. The results will have little impact on guidelines and practice in the wealthy countries, but will greatly affect resource-limited countries that until now have restricted treatment to those with lower CD4. New WHO guidelines will recommend ART for all. Delivering care consistent with these new guidelines will represent a huge challenge for public health officials and agencies that fund HIV care in limited-resource areas. Before START, many patients diagnosed with high CD4 were told treatment was not necessary, sending a message that early HIV is not a serious health problem. This message feeds patient denial and may lower motivation for some to remain in care or to remain adherent to ART when prescribed. Health care providers may now tell all patients with HIV they have serious infection that requires treatment.
IAS: START Trial: Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection......The START trial was designed and conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)..... - (07/24/15)
IAS: Strategic Timing of AntiRetroviral Treatment (START) Study Primary Results - (07/22/15)
ART in Women. Although women represent about half of all cases of HIV globally, they are almost always underrepresented in clinical trials of ART. Although there is some data to suggest that safety, tolerability and efficacy of ART may differ between the sexes, very few studies have formally compared ART outcomes in women. The WAVES study was a double-blind, placebo controlled trial conducted in 575 treatment-naive women [3]. The majority were enrolled in Russia, Uganda and the USA. Participants were randomized to fixed-dose tenofovir/emtricitabine/elvitegravir/cobicistat (TEEC) or tenofovir/emtricitabine plus atazanavir and ritonavir (TEAR). Using the FDA snapshot analysis and an HIV RNA threshold of <50 copies, at 48 weeks 87% of women on TEEC were treated successfully compared to 81% on TEAR. The difference of 6.5% was statistically significant (95% CI 0.4%-12.6%; p=0.03). The outcome was driven by a higher rate of discontinuations for adverse events in the TEAR arm, especially for skin eruptions. As would be expected, jaundice and hyperbilirubinemia were much more common in the atazanavir-containing arm, but led to few discontinuations. Nausea, vomiting, renal function, bone-mineral density and lipid changes did not differ except for a small but clinically trivial greater increase in total cholesterol with TEEC. In WAVES, both regimens were reasonably safe and effective but there was modest advantage for TEEC. A previous study conducted in a male-predominant study population recruited in Australia, Europe, North America and Thailand showed non-inferiority of these same regimens and the rate of discontinuations for drug eruptions was far lower [4]. The observed differences between these two trials may be attributable to gender or genetic differences between the study populations, or both. Current DHHS guidelines recommend integrase inhibitor-based (including TEEC) or darunavir-based ART for initiation of therapy, but for women who are pregnant, planning pregnancy or not using effective contraception, safety in pregnancy is an important consideration when choosing ART. In such patients atazanavir will remain a reasonable choice until there is sufficient safety data in pregnancy for elvitegravir and cobicistat.
IAS: Elvitegravir (EVG)/Cobicistat (COBI)/Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF) Is Superior to Ritonavir (RTV)-Boosted Atazanavir (ATV) Plus FTC/TDF in Treatment-Naïve Women With HIV-1 Infection (WAVES Study) - (07/21/15)
Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial - (09/20/12)
New Antiretrovirals in Existing Classes. The NNRTI class of antiretrovirals has been widely and successfully used in clinical practice, yet no currently approved NNRTI has ideal features. Efavirenz has frequent although usually transient neuropsychiatric adverse effects and an association with suicidality. Rilpivirine is somewhat less potent. Nevirapine has both lower potency and greater toxicity. Etravirine is active in many efavirenz-experienced patients but its role in initial therapy has not been adequately defined. All NNRTIs have a low genetic barrier to resistance. As a consequence, the DHHS guidelines no longer include NNRTIs among the recommended regimens. Doravirine (MK-1439) is an investigational NNRTI that is dosed once daily and in vitro develops resistance by a unique pathway that does not overlap those of current NNRTIs. Gatell et al [5] presented data from an open-label study that combined 205 patients randomized to doravirine 100 mg daily or efavirenz in a dose-ranging study with additional patients randomized between only these two treatment options. All participants also received tenofovir/emtricitabine. At 24 weeks, 73% and 72% on doravirine or efavirenz, respectively, had HIV RNA <40 copies/mL. Thirty-six percent of enrollees had a baseline HIV RNA >100,000 and in this subset the corresponding numbers were 61% and 65%. These response rates seem low by the standard of most recent ART trials, but may be due to the use of a more sensitive HIV RNA assay, the relatively high proportion of high viral load participants and the early time point (24 weeks) for the analysis. There were only 4 doravirine recipients considered virologic failures at week 24 that had HIV RNA >200 (vs. 1 on efavirenz). The authors suggested these viral loads were still declining from high baseline values at week 24 and might well be successes by 48 weeks. There were fewer neuropsychiatric adverse effects and fewer discontinuations with doravirine. Doravirine appears to have desirable characteristics that could improve upon those of currently licensed NNRTIs. Additional data from this study and from larger trials will be needed to assure that doravirine 100 mg daily is optimally potent, and to establish its resistance profile and long-term safety.
IAS: Efficacy and Safety of Doravirine 100mg QD vs Efavirenz 600mg QD with TDF/FTC in ART-Naive HIV-Infected Patients: Week 24 Results - (07/22/15)
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, is generally safe, effective, and well tolerated. Still, in some patients it causes declines in glomerular filtration rate (GFR), proximal renal tubule dysfunction and may exacerbate the decline in bone mineral density (BMD) associated with ART initiation. Tenofovir alafenamide (TAF), an investigational alternate prodrug of tenofovir, is in late stage clinical development. It achieves high concentrations in lymphocytes of tenofovir diphosphate, the active form, with lower plasma concentrations. The results of a recently published trial demonstrate that TAF has similar efficacy with less renal and bone adverse effects than TDF [6]. Mills et al presented results of a large, open-label switching study that enrolled 1436 patients virologically suppressed on a TDF-containing regimen that included emtricitabine plus either efavirenz, atazanavir/ritonavir or elvitegravir/cobicistat [7]. Participants were randomized 2:1 to switch to the fixed-dose combination of TAF, emtricitabine, elvitegravir and cobicistat (TAF-EEC) or remain on their current regimen. After 48 weeks, significantly more patients who switched were successfully treated (97% vs. 93%), a small but statistically significant (p<0.001) difference driven by a combination of more discontinuations for adverse events and more missing 48 week data in the TDF arm. Those switched from the efavirenz or atazanavir-containing regimens fared better but those on an elvitegravir-containing regimen at entry had similar treatment success with either TDF or TAF. Both low-molecular weight proteinuria and albuminuria declined significantly and bone mineral density improved in those who switched to TAF. Symptomatic and laboratory adverse events were similar. Changes in serum creatinine were not presented, but those whose baseline regimen contained ritonavir or cobicistat, both inhibitors of creatinine secretion, had declines in serum creatinine after the switch to TAF-EEC. In this study, 2/3 of participants randomized to switch changed the third agent as well as switching TDF to TAF, so the advantage in treatment success (the primary end-point) seen in the switch arm is mostly attributable to the better tolerability of elvitegravir/cobicistat rather than differences between TDF and TAF. The improvement in bone and renal parameters is most likely due to switching from TDF to TAF, although some improvement in BMD could have resulted from switching of third agents to the integrase inhibitor.
A second study evaluated the safety of TAF in 242 patients on stable ART, with or without TDF, and reduced kidney function as evidenced by an eGFR between 30-69 mL/min [8]. Participants were switched from their current regimen to TAF-EEC. Sixty-five percent were using TDF in the baseline regimen. True GFR, measured by iohexol clearance in a subset of participants, was stable through week 24, regardless of the presence or absence of TDF in the baseline regimen. Other assessments were done at 48 weeks and results differed depending on whether or not the baseline regimen contained TDF. Proteinuria (both low-molecular weight and albumin) declined and bone mineral density increased in those switching off TDF while those not on TDF at baseline had no change. Lipid values increased in those switching off TDF while those not on TDF had declines, probably due to lesser effect on lipids of elvitegravir compared to other 3rd agents used in the baseline regimens, or possibly a modest lipid lowering effect from TAF. The study design, which serves the commercial interests of the manufacturer, confounds the interpretation of standard creatinine-based equations for GFR estimation, since TAF-EEC contains the inhibitor of creatinine secretion cobicistat. When using a cystatin C-based equation (CKD-EPIcysC), those switching from TDF had a small (2.7 mg/dL) but statistically significant improvement in GFR. The meaning of this small change is unclear, since true GFR didn't change at 24 weeks, was not measured in all participants, and was not reassessed at 48 weeks.
These studies confirm that TAF has less renal and bone effects than TDF, but the clinical significance remains uncertain. Subclinical proteinuria, especially of low molecular weight proteins, is common in patients treated with TDF, but does not predict progressive renal tubular abnormalities, Fanconi syndrome or loss of GFR. It has not yet been shown that switching to TAF will reduce the need to treat osteoporosis, bone fractures or clinically overt renal disease. Approval of TAF is anticipated shortly. Since TDF is well tolerated by most patients, if TAF is substantially more expensive it may be reserved for those who have preexisting renal or bone disease or prior adverse effects on TDF, especially if generic TDF becomes available in the next few years.
[From Jules: John Winston, MD, Mt Sinai Hospital NY, a noted kidney expert, from personal communication said to me the results of improved kidney function are proof of concept and so we expect these improvements will be reflected in clinical benefit but it will take collecting followup data for as much as 5 years to establish the proof.]
IAS: Switching From a Tenofovir Disoproxil Fumarate (TDF)-Based Regimen to a Tenofovir Alafenamide (TAF)-Based Regimen: Data in Virologically Suppressed Adults Through 48 Weeks of Treatment - (07/22/15)
IAS: Subjects with Renal Impairment Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Have Improved Renal and Bone Safety through 48 Weeks Study GS-US-292-0112 - (07/22/15)
Drugs with Novel Mechanisms. The antiretroviral armamentarium is currently stocked with many potent and tolerable agents with varying mechanisms of action. Most patients can now be managed successfully with these drugs. Still, in certain patients treatment fails due to adverse effects, transmitted or acquired drug resistance, or the requirement for a high level of adherence to daily medication. For such patients, new drugs with novel mechanisms of action are needed. Data on two such drugs being developed by Bristol-Myers Squibb were presented.
BMS 955176 (176) is HIV maturation inhibitor that works by binding to the p24 capsid protein-space peptide1 cleavage site of the gag polyprotein, preventing protease mediated cleavage, leaving the HIV core incompletely assembled [9]. As with protease inhibitors, virions produced in the presence of this drug are non-infectious. It has activity against gag gene variants that confer to resistance to beviramat, an earlier candidate maturation inhibitor [9]. HIV RNA declines of >1 log were seen in a 10 day monotherapy trial with 40, 80 and 120 mg daily of BMS 176. Hwang et al. presented a small combination therapy trial in which participants were randomized to treatment with 40 mg BMS 176 plus either boosted or unboosted atazanavir, 80 mg BMS 176 plus unboosted atazanavir (n=8 for each group) or a standard ART arm with TDF/emtricitabine/boosted atazanavir (n=4) for 28 days [10]. Maximum HIV RNA declines of slightly more than 2 logs were seen with 40 mg plus boosted atazanavir and 80mg plus unboosted atazanavir and with standard ART. A single grade 3-4 adverse event (neutropenia) was observed. Bilirubin elevation due to atazanavir were also seen. BMS 176 is a promising antiretroviral with a novel mechanism of action that could be useful in heavily treatment-experienced patients. However there appears to be a wide range of susceptibility among naturally occurring HIV strains. A minority may be naturally resistant. It is also unclear if subtypes other than B are susceptible to BMS 176. Larger studies are underway.
IAS: Second-Generation HIV-1 Maturation Inhibitor BMS-955176: Antiviral Activity and Safety with Atazanavir ± Ritonavir - (07/22/15)
BMS 663068 (068), the prodrug of an HIV attachment inhibitor is another novel investigational antiretroviral. It binds to HIV envelope protein gp120 to prevent the conformational changes needed to expose the CD4 binding site.
Naturally occurring HIV strains exhibit a wide range of susceptibility to BMS 626529, the active form of BMS 068, but most have an 50% effective concentration (EC50) <10nM [11]. In a previously reported trial, clinically important virologic activity was seen in treatment-experienced patients receiving 7 days of monotherapy followed by 47 weeks of combination therapy adding multiple active agents, and no serious safety signals were observed [12]. Lataillade et al [13] analyzed HIV isolates from this trial to try to discern a correlation between baseline phenotypic or genotypic resistance and treatment failure. No correlation was found, although few isolates with an EC50 >10nM were studied and patients whose isolates had an EC50 >100nM (6% of those screened) were excluded from the treatment trial because a previous study suggested they respond less well to BMS 068 [14]. Among treatment failures, the majority had 10-fold or greater increase in EC50 and emergent gp120 mutations previously found to confer resistance. Several isolates developed >100-fold resistance from baseline. This novel attachment inhibitor has promising activity and safety that could be useful in treatment-experienced patients with multi-class antiretroviral resistance. However, it appears the drug has a low genetic barrier to resistance and not all naturally occurring isolates will be susceptible. The lack of a correlation between baseline susceptibility and treatment success may have been masked by the addition of 2 or more active agents in the background regimen. Phase 3 clinical trials are ongoing. An important unanswered question is whether clinical use of this drug should be preceded by a specialized phenotypic assay to document susceptibility, a requirement that has blunted the uptake of CCR-5 inhibitors, and if so, what the cut-off for susceptibility should be.
IAS: HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Analysis of Emergent Viral Drug Resistance Through 48 Weeks of Follow-Up - (07/24/15)
(studies over the years) HIV-1 Attachment Inhibitor Prodrug BMS-663068: Assessment of Interactions with
Raltegravir in Treatment-Experienced HIV-1-Infected Subjects & Efficacy/Safety.......http://www.natap.org/2015/Pharm/Pharm_29.htm
IAS 2015: 8th IAS Conference on HIV Pathogenesis Treatment and Prevention
Vancouver Canada18-22 July 2015
References.
1. Lundgren J, et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract MOSY0302.
2. The INSIGHT START study group. New Engl J Med DOI: 10.1056/NEJMoa1506816. Published on-line July 20, 2105 at NEJM.org
3. Squires K et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract MOLBPE08.
4. DeJesus, E et al. Lancet 2012;379:2429-38.
5. Gatell J, et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0104.
6. Sax PE, et al. Lancet 2015; 385: 2606-15.
7. Mills A et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0102
8. Gupta S et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0103
9. Nowicka-Sans B, et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUPEA078
10. Hwang et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0106LB
11. Nowicka-Sans B et al. Antimicrob Agents Chemother 2012; 56:3498-3507.
12. Thompson M, et al. Attachment inhibitor prodrug BMS-663068 in ARV-experienced subjects: Week 48 analysis. Abstract 545, CROI 2015, Seattle, WA, Feb 23-26, 2015.
13. Lataillade M, et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUPEB284.
14. Nettles R, et al. J Infect Disease 2012;206:1002-11.
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