HIV10 November 7-11, 2010 Glasgow, Scotland

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1 HIV1 November 7-11, 21 Glasgow, Scotland Course Director Calvin Cohen, MD, MS Research Director, CRI New England Clinical Instructor, Harvard Medical School Boston, Massachusetts Faculty José Arribas, MD Senior Attending Physician, HIV Care Unit Hospital de La Paz Madrid, Spain Graeme Moyle, MD, MB, BS Associate Director of HIV Research, Chelsea & Westminster Hospital London, England Jürgen K. Rockstroh, MD Professor, University of Bonn Bonn, Germany Introduction The following is a summary of talks presented during the online CME symposium, ARV Therapies and Therapeutic Strategies, which described key studies on antiretroviral (ARV) therapies and therapeutic strategies presented at the Tenth International Congress on Drug Therapy in HIV Infection (HIV1), in Glasgow, Scotland. The faculty panel included Course Director and Moderator Dr. Calvin Cohen, Harvard University, Boston, Massachusetts; panelists Dr. Jürgen Rockstroh, the University of Bonn, Bonn, Germany; Dr. José Arribas, Hospital de la Paz, Madrid, Spain; and Dr. Graeme Moyle, Chelsea & Westminster Hospital, London, England. Treatment of ARV-naïve Patients Dr. José Arribas There have been changes in the three main HIV treatment guidelines those from the US Department of Health and Human Services (DHHS), the International AIDS Society (IAS) and the European AIDS Clinical Society (EACS) during the past year. The guidelines agree that clinicians should start ARV treatment in patients with CD4 cell counts <35 cells/mm 3. What is new this year are data on when to start therapy for patients with low CD4 cell counts and opportunistic infections. ACTG 5164 showed that for patients with opportunistic infections (OIs), it is better to start treatment within two weeks of the diagnosis of the OI. 1 This year saw publication of the South African Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy (SAPiT) trial, which included 642 patients with active tuberculosis (TB). The trial examined the question: when is it better to start highly active antiretroviral therapy (HAART) in patients with active TB? There were three arms in the trial: one started ARV treatment during TB treatment, during the first two months; the second arm started ARV treatment during the second phase of anti-tb treatment, from month 2 to month 6; the third consisted of starting HAART after finishing TB treatment. 2 The trial was stopped early because the arm that was receiving HAART after finishing TB treatment had a significant decrease in survival (Figure 1). The data on the integrated part of the treatment (anti-tb treatment + HAART) has not been released, so we do not know if patients who were treated in the intensive part of anti-tb treatment were better prepared than patients who were treated after they finished the intensive part, but the clear message in this trial is that clinicians should not wait to treat HIV until treatment of TB is finished. Figure 1. Results from the SAPiT Trial 2 1. Kaplan-Meier Survival Curve.95 Integrated Arm Survival Sequential Arm P=.3 Supported by an unrestricted educational grant from Merck & Co., Inc. *This coverage is not sanctioned by the conference organizers and is not an official part of the conference proceedings..75 Intensive Continuation Post-TB Treatment Phase Phase of TB of TB Treatment Treatment Months After Randomization 1. Zolopa A, et al. 15th CROI; Boston, MA; February 3-6, 28. Abst Abdool Karim S, et al. 16th CROI; Montreal, Canada; February 8-11, 29. Abst. 36a. 1

2 The CAMELIA clinical trial was another trial on late versus early treatment for patients with TB. The investigators randomized patients with active TB to start ARV therapy at two weeks versus eight weeks. 3 The patients in this study were very sick: the median CD4 cell count was 25 cells/mm 3 (in the SAPiT trial, the median CD4 cell count was around 15 cells/mm 3 ). In this sicker population of patients with active TB and low CD4 cell counts, patients randomized to receive ARV therapy early had increased survival compared with patients who received treatment eight weeks after starting anti-tb treatment. Therefore, this study is another confirmation that in patients with very low CD4 cell counts and active TB, it is important to start ARV therapy as early as possible. When comparing the major guidelines, differences begin to appear concerning the management of HIV+ patients with CD4 counts >35 cells/mm 3. In patients with CD4 cell counts between 35 and 5 cells/mm 3, the DHHS guidelines recommend starting treatment but they offer, for the first time, the results of the voting of the panel that developed the guidelines. The panel was split: 55% voted for a strong recommendation and 45% voted for a moderate recommendation for treatment. The IAS guidelines recommend starting therapy between 35 and 5 cells/mm 3, and the EACS guidelines recommend deferring treatment. However, those guidelines say treatment should be recommended between 35 and 5 cells/mm 3 if the patient has hepatitis C virus (HCV) co-infection, hepatitis B virus (HBV) co-infection requiring therapy, HIV-associated nephropathy or any other specific organ deficiency; and treatment should be considered if viral load is >1, copies/ml, if there is a rapid decline in CD4 count, if patients are >5 years of age, pregnant, or have high cardiovascular or malignancy risk. When an HIV+ patient has >5 CD4 cells/mm 3, the DHHS panel is divided: their view of treatment is recommended or optional. The IAS recommendation is to consider ARV therapy in patients >5 CD4 cells/mm 3 with few exceptions: if the patient is an elite controller or has stable CD4 cell counts. For these patients, the EACS recommendation is to defer therapy, with the exception of patients with certain co-morbidities. Earlier treatment is recommended regardless of CD4 count for symptomatic AIDS in all three guidelines; they also recommend early treatment if the patient has HBV co-infection, HIV nephropathy, or pregnancy. If a patient has a rapid CD4 decline, this is also a situation that has to be considered regardless of CD4 cell count. For a patient with HCV, the DHHS guidelines do not consider treatment, regardless of the CD4 cell count, while in the IAS and EACS guidelines, it is a situation in which ARV treatment is recommended. Age is also a factor in treatment the IAS guidelines recommend treatment for patients >6 years and the EACS guidelines recommend treatment for patients >5 years. 3. Blanc F, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. THLBB16. High cardiovascular risk is another issue to consider, regardless of CD4 cell count in the IAS (treatment recommended) and EACS (consider treatment) guidelines. Malignancy is only addressed in the EACS guidelines (consider treatment). And for the first time, the IAS guidelines recommend therapy when the risk for secondary HIV transmission is high, regardless of CD4 cell count. The guidelines also provide guidance concerning starting ARV therapy for treatment-naïve patients. Several regimens are recommended in all the three guidelines: efavirenz (EFV)/ tenofovir (TDF)/emtricitabine (FTC); darunavir/ritonavir (DRV/r) + TDF/FTC; atazanavir/ritonavir (ATV/r) + TDF/FTC; and raltegravir (RAL) + TDF/FTC. The results of ACTG A522 were presented at the Conference on Retroviruses and Opportunistic Infections (CROI). 4 This was a large trial of drugs that are currently in use. It had a factorial design where patients were randomized to receive a third drug, either EFV or ATV/r, with nucleosides TDF/FTC or abacavir (ABC)/lamivudine (3TC). In this clinical trial, researchers were comparing two different strategies a boosted protease inhibitor (PI) versus a non-nucleoside reverse transcriptase inhibitor (NNRTI) and different nucleoside backbones. At baseline, patients had a median HIV RNA of 4.6 to 4.7 log 1 copies/ml. The Data and Safety Monitoring Board (DSMB) found that patients with a baseline viral load >1, copies/ml randomized to ABC/3TC had a higher risk of virologic failure than patients randomized to TDF/FTC, so they stopped that part of the trial while continuing the comparison in patients with viral loads <1, copies/ml to continue (Figure 2). Figure 2. A522: Time to Virologic Failure in Patients with Baseline HIV RNA >1, copies/ml 5 Probability of No Virologic Failure (%) Weeks Since Randomization TDF-FTC (26 events) ABC-3TC (57 events) P<.1, log-rank test Hazard ratio, 2.33 (95% CI, ) Results similar between EFV and ATV/r arms Ultimately, the study found no difference between TDF/FTC and ABC/3TC in patients with viral loads <1, copies/ml. When all the subjects included in the trial are examined (regardless of HIV RNA viral load), ATV/r performed as well as EFV. The overall efficacy rates at 96 weeks were close to 9% for all groups. 4. Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 21. Abst. 59LB. 5. Sax PE, et al. N Engl J Med 29;361:

3 When comparing a boosted PI and an NNRTI, apart from efficacy, it is important to see the consequences of failure. In this study, when patients failed on an EFV-containing regimen, there were nucleoside reverse transcriptase inhibitor (NRTI) mutations and NNRTI mutations. The overall rate of any major mutation was higher than that observed in patients taking ATV/r. On ATV/r, there were almost no primary PI mutations, and there was a lower rate of nucleoside mutations. Another interesting study compared the activity of PIs versus NNRTIs using an ultrasensitive polymerase change reaction (PCR) test in patients whose HIV RNA was <5 copies/ml. 6 The results suggested that the proportion of patients with <3 copies/ml was higher in an NNRTI-containing regimen than with a PI-containing regimen and that this may reduce the risk of virologic failure. Another study discussed at the conference was SENSE, a trial of ARV-naïve patients that compared etravirine (ETR) with EFV. 7 ETR is used mostly in rescue settings; less information is known on its use in ARV treatment-naïve patients. SENSE was a small clinical trial (N=157). The primary endpoint was the number of central nervous system (CNS) adverse events related to the drug that were seen after 12 weeks of treatment. At 12 weeks, there were fewer CNS adverse events in the ETR arm than in the EFV arm: 16.5% versus 46.2% (P<.1). The major treatment guidelines all recommend the same paradigm for starting ARV therapy: two NRTIs + a third drug. This year, there were preliminary data presented on a different paradigm: a boosted PI plus another class of drug, such as an integrase transfer inhibitor or a CCR5 inhibitor. In the PROGRESS study, which was presented at the International AIDS Conference (IAC) in Vienna this year, ARV-naïve patients received either lopinavir/ritonavir (LPV/r) + RAL or LPV/r + TDF/ FTC (N=2). 8 Patients in the study had a relatively low viral load (about 1, copies/ml). The preliminary findings have been presented. The arm with RAL had a rapid decline in viral load, and after one year of follow-up, it appears that this combination was effective in a population with relatively low viral loads. Treatment Experienced Patients, New Drugs and Issues in Virus Resistance Dr. Calvin Cohen Data from the United States over the past few years shows that 16% of treatment-naïve HIV+ patients have transmitted drug resistance. Of this 16%, in about half of cases it is NNRTI resistance; 6% have NRTI resistance, and 4% have PI resistance. That last number may continue to decline, because clinicians are creating fewer PI mutations. Nevertheless, because of the 6. Maggiolo F, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O Stellbrink HJ, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O Reynes J, et al. 18th IAC; Vienna, Austria; July 18-23, 21; Abst. MOAB11. popularity of NNRTIs and the potential for NNRTI resistance, this 8% continues to be a concern. OCTANE 1, a randomized trial of TDF/FTC with either LPV/r or NVP, enrolled women who had previously received a single dose of nevirapine (NVP) to prevent mother-to-child transmission. 9 As a result, they had developed some degree of NVP resistance. In patients taking LPV/r, the risk of failure was 9%, and on NVP it was variable (14% to 41%). The variable that predicted failure was not based on standard resistance testing, but on resistance testing using allele-specific PCR (ASP), a methodology that can detect extremely low levels of mutations (<1%). In patients who, by standard genotyping, were considered to have wild-type virus, there was no evidence of NNRTI resistance. If on ASP they had mutations present, 32% had virologic failure; if they were negative by ASP, then they had a 13% failure rate, suggesting that transmitted drug resistance estimates by standard genotyping may underestimate the risk and consequences of resistance. On the subject of genetic barriers, there was a study presented at the International HIV and Hepatitis Drug Resistance Workshop that examined the risk of either EFV or RAL and nucleoside resistance in the STARTMRK trial. 1 In this study, patients were randomized to TDF/FTC + either EFV or RAL. It was reported that in patients with virologic failure on EFV, about one third developed EFV resistance only, while an additional 45% developed EFV and 3TC or FTC resistance (M184V) simultaneously. In contrast, no patients developed RAL resistance alone, and only about 1% developed RAL resistance and M184V simultaneously. The most common pattern for patients on RAL was M184V alone, suggesting that although RAL is one mutation away from resistance, the timing of resistance is faster for EFV than it is for RAL. This suggests that the genetic barrier may be a little bit better in RAL than in EFV at least in failing patients. The SPIRAL study enrolled a well-suppressed population on boosted PIs, and randomized them to stay on a boosted PI or substitute RAL. In this study, RAL did as well as the boosted PIs in maintaining suppression. 11 The suppression demographics were not substantially different from those seen in SWITCHMRK. The reason why this study may differ is the duration of suppression on the two NRTI-boosted PI regimens was extensive, about 6 years. It was hypothesized that even if there was pre-existing treatment failure and NRTI resistance, it was sufficiently long ago that the importance of these mutations may have diminished. However, it is still not clear why the results of these two studies were different. The data were reassuring, because they indicated that in some patients, such as those with 9. Boltz V, et al. 17th CROI; San Francisco CA; February 16-19, 21. Abst Miller M, et al. International HIV and Hepatitis Drug Resistance Workshop; Dubrovnik, Croatia; June 8-12, 21; Abst Martinez E, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. MOAB13. 3

4 wild-type virus who were suppressed, clinicians should be able to use RAL as a substitution without concern, and perhaps even in other settings. Another difference that may be important between both trials is that SWITCHMRK was double-blind and double-dummy, and patients had to take more pills than in SPIRAL. Adherence may have been better in SPIRAL than in SWITCHMRK. The SPIRAL study was open-label, so it would be easier to adhere to the RAL regimen. Another study of interest was the BENCHMRK study. There were some patients who received very compromised regimens in some subsets of the BENCHMRK study. An analysis 12 was conducted that studied what would happen if RAL or DRV/r was the only active drug with a compromised background. At both week 48 and week 156 of this study, it was shown that if RAL was the only fully active drug, about half of the patients responded and stayed suppressed for three years. When DRV/r was the only active drug (when RAL was not given), a similar number, around 5%, were suppressed. So, patients taking RAL and DRV/r did well using the lower cut off to determine the activity of the drugs. If we use the upper cut off to determine the activity, with RAL plus a very compromised background, again about 5% responded, but if DRV/r was used, then DRV/r did not do as well as RAL. These findings support the view that RAL and a compromised background do as well as a fully active PI and a very compromised background. Rilpivirine (RPV) versus EFV was studied in two large studies: ECHO and THRIVE. The two studies are similar except for a difference in the choice of NRTI. Both are doubleblind, double-dummy studies with EFV and RPV. ECHO had TDF/FTC for all patients, and in THRIVE there was a choice of NRTI, although 6% receive TDF/FTC. Because of the doubledummy design, RPV was taken with food, while EFV was taken without food at bed time. So it was not a QD regimen it was at least a BID regimen. Patients could take their NRTI at the same time, though. In the Intent-to-Treat results, there were similar rates of suppression; the RPV was not inferior to EFV in overall rates. There was about a 4% higher rate of virological failure on RPV than EFV; and there were about 5% more dropouts or discontinuations for adverse events, in EFV that RPV. Were there predictors as to why RPV had a somewhat higher virological failure rate? This was examined in an analysis presented at HIV1. 13 It was based on a questionnaire called the Medication Adherence Self-Report Inventory (MASRI), which is a self-report questionnaire based on the previous 3 days. It was found that patients who reported >95% adherence over the year on RPV or EFV had about an 88% response rate. In patients who reported 9% to 95% adherence, both drugs were less active both around 75% to 78% responding. In patients 12. Rockstroh J, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. P Cohen C, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O48. who were <9% adherent, both drugs had a virologic response around 5%, with RPV (51%) a bit less than EFV (59%). So both drugs were impacted by adherence. The other factor that was found to impact outcome was baseline viral load. Patients who were >1, copies/ml on RPV had slightly more virologic failure than those on EFV, while the overall results showed non-inferiority for RPV. In patients <1, copies/ml, there was a 9% response for RPV versus 84% for EFV, and there were low rates of virological failure in both groups. In fact, the only difference was a few more discontinuations for adverse events with EFV. So, certainly for patients with <1, copies/ml, RPV has good results, and perhaps even better results numerically. This study enrolled some people with very high viral loads, which is the group that may have been responsible for many of the treatment failures. It is worth considering that the numbers at the highest end of the high viral loads were small only 35 people per arm so we should be cautious not to draw too many conclusions from these data. While there is a clear viral load effect, more work is needed, including additional analysis, to make sense of the discrepant data from the two studies. Still, it appears clear that below 1, copies/ml, there is no concern for the activity of RPV. In the failing patients, there was resistance to the NRTIs and to EFV and RPV. The NRTI resistance was more likely on RPV than EFV. In terms of NNRTI resistance, the frequency was the same in the two drugs, but the mutations differed. On RPV, it was 138K; on EFV, it was 13N. It is known that 138K creates resistance not just to RPV but also to ETR. 13N is not known to create resistance to ETR, so that also has been a choice of discussion; nevertheless, the failure rates were pretty low in this trial, overall. Researchers have been investigating the combination of elvitegravir (EVG), a new integrase inhibitor, with cobicistat (CBS) and 48-week results were reported from two phase II 14, 15 studies that assessed these drugs in treatment-naïve patients. In one of the studies, EVG and CBS were combined in a single tablet with TDF/FTC (quad), and it was compared with the standard EFV/TDF/FTC single tablet. A second study compared CBS or ritonavir (RTV or /r), in a regimen of TDF/FTC and ATV. In terms of the quad versus the standard three drug tablet, at 48 weeks both had similar efficacy of nearly 9%. EVG, like other integrase inhibitors, has a more rapid response, but despite EFV working more slowly, by week 48 the response was similar. With ATV, the response was similar as well, with 82% to 86% of treated patients with HIV RNA <5 copies/mm 3 at week 48 (Figure 3). These results demonstrated that both drugs accomplish what they were designed to do, and justify the phase III studies that are now fully enrolled. 14. Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 21. Abst. 58LB. 15. Elion R, et al. 5th ICAAC; Boston, MA; September 12-15, 21. Abst. H-938b. 4

5 Figure 3. Elvitegravir and Cobicistat Phase 2 Studies: Patients with HIV RNA <5 copies/ml at 48 Weeks 15 Percentage with HIV RNA <5 copies/ml EVG/c vs. EFV 2 W48 95% CI: -8.8% to 25.6% Week EVG/c/TDF/FTC EFV/TDF/FTC 9% 83% Percentage with HIV RNA <5 copies/ml ATV/r vs. ATV/c 2 W48 95% CI: -21.7% to 12.5% Week ATV/r + TDF/FTC ATV/c + TDF/FTC 86% 82% Another integrase inhibitor being investigated is S/GSK 572 (572). In the SPRING study, there were three doses that were compared to EFV. All patients received two NRTIs. In the results presented at HIV1 in Glasgow, there was excellent efficacy in all three doses of 572, with over 9% response rates at week The EFV arm had a lesser response rate, but the data presented suggest that with time this may improve beyond 24 weeks. The response to treatment was reported to be similar whether patients had viral loads less than or greater than 1, copies/ml. The non-response discontinuation for adverse events was very low on 572, and there were no 572 signature toxicities. No integrase inhibitor-associated resistance has been detected in the few patients who failed. While clinicians do not see a lot of cases of RAL failure, it can occur. An analysis of VIKING, which explored the use of 572 following RAL failure, was presented at HIV1. 17 In this single arm trial with 3 patients, when 572 was given to patients with a compromised background, very few patients responded. However, when 572 was given with an active two-drug background, most patients reached <4 copies/ml, and many were <5 copies/ml. With the exception of some RAL-resistant virus with multiple mutations, a number of the patterns, including the most common pattern, did suppress when 572 was given with an active regimen (Figure 4). Figure 4. VIKING: Proportion of RAL-resistant Responders by Optimal Background Regimen (OBR) Activity <5 copies/ml <4 copies/ml Overall 1 >2 No. of subjects Phenotypic Susceptibility Score of OBR (Day 11) Proportion (%) 16. Rockstroh J, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O Min S, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O51. Another study presented at IAC 21 in Vienna was the ODIN trial, in which patients received DRV/r. 18 This study involved DRV-naïve patients who had been treated with other regimens. The question explored was, if a patient had not taken DRV and had DRV-susceptible virus, was it effective to use DRV/r at the standard once-daily dose, or do patients need to take twice-daily DRV/r? The investigators reported that in adherent patients, patients taking once-daily and twice-daily DRV/r did well, at roughly 85% efficacy for both groups. However, in suboptimally adherent patients, neither dosage did as well, but there was no evidence of differences between the two dosage groups. These findings support the view that in treatment-experienced patients with DRV-susceptible virus, the once-daily dose is an acceptable option. Toxicities and Adverse Events Graeme Moyle, MD Many clinicians are concerned that the population of people with HIV is aging. In some cohorts, >2% of patients are over the age of 5 years. So there is an increased interest in diseases of aging, which may be occurring at an earlier age in people with HIV infection. One of the primary concerns of clinicians along these lines is cardiovascular disease (CVD). The DAD study raised the question whether exposure to PIs is associated with CVD. It pinpointed LPV/r and indinavir (IDV) as being relevant, and some other cohorts supported LPV/r as a concern regarding CVD. And there is also the analysis of SMART, which suggested that people receiving ABC currently may have a greater risk of CVD. A meta-analysis was conducted by a group in Italy, using the methodology set up by the Cochrane group. They examined data from all of the available sources of randomized control trials that were based around ABC regimens. 19 They found that across the studies, very small numbers of individuals experienced myocardial infarction (MI) events. Out of over 66 patients followed for a minimum of 24 weeks, with some beyond 96 weeks, there were only 11 MIs with ABC and 15 in the control group. There have been those who argue that a cohort study may pick up a signal with ABC that is then not supported by clinical trial data. It could be that the DAD study included more patients with high risk of CVD, whereas treatment-naïve patients predominantly in their 3s do not get pre-existing plaque disease, which might then be disturbed by ABC. What is clear from randomized controlled comparisons, such as the HEAT study or ASSERT, is that there are differences in the lipid profile between TDF and the NRTIs, including ABC. ASSERT was a randomized, controlled study, across Europe, comparing ABC/3TC and TDF/FTC with EFV. The 96-week data were reported at the International Workshop on Adverse Drug Reactions 18. Workman C, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. TUPE Cruciani M, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. WEPE121. 5

6 and Lipodystrophy in HIV. 2 For all key lipid parameters, there were smaller increases in the TDF group. Other studies have found the same thing. In PROGRESS, which compared LPV/r + RAL to LPV/r + TDF/FTC, lipids were better in the arm with TDF than with RAL, and in ATLAS, the lipids got worse when patients stopped taking TDF. These findings were supported by ACTG Whether EFV was the partner or ATV/r was the partner, there was a bigger increase in lipids in the ABC/3TC group relative to the TDF/FTC group. Another study that was presented in more detail at HIV1, but initially presented at IAC 21, was the METABOLIK study, which was the first comparative study of ATV/r and DRV/r. 22 It only had 32 patients per group, so we cannot make any judgments about the efficacy within the regimen. What was found for both drugs was that they have remarkably similar metabolic changes, although there were slightly smaller changes with the ATV/r group, particularly with regards to triglycerides. In studies like CASTLE, where there are differences between LPV/r and ATV/r or DRV/r, it is driven by the amount of RTV patients receive, and once patients are reduced to 1 mg of RTV per day, they will probably start to get a limited effect on lipids. So, when we compare two regimens that are based around 1 mg of RTV per day, with the TDF/FTC backbone, we see a minimal change in lipids, and would conclude that these are relatively metabolically benign regimens. The lipid effect of CBS has also been studied. The overall impression from research has been that CBS is similar to RTV with respect to lipids, except for triglycerides. Triglycerides are a concern with RTV, because its use has been associated with increased triglycerides. There may be some subtle advantages in terms of CBS s effect on lipids relative to what we see with RTV. When we look at the comparison of TDF/FTC/EFV that was presented at ICAAC 21, 23 we see there was a lesser effect on total cholesterol and LDL with the CBS group, but a greater effect on triglycerides (Figure 5). So, the CBS-based regimen or the RTV-based regimen had a lesser effect than EFV. Figure 5. Cobicistat-based Regimens vs. Comparators: 23 Lipid Changes at Week 48 Change from Baseline to Week 48 (mg/dl) TDF/FTC/EVG/c TDF/FTC + ATV/c TDF/FTC/EFV TDF/FTC + ATV/r TC LDL HDL TG 2. Moyle G, et al. 12th ADRL; London, England; November 4-6, 21. Abst. O Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 21. Abst. 59LB. 22. Aberg J, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. WEPE Elion R, et al. 5th ICAAC; Boston, MA; September 12-15, 21. Abst. H-938b. The data from two studies, ECHO and THRIVE, were combined for analysis. 24 In these studies, there were two agents, RPV and EFV, that performed similarly from an efficacy stand point. However, there were small difference in terms of tolerability. As with other studies of EFV, in this analysis EFV caused a rise in total cholesterol and around a 2 mg/dl increase in triglycerides. However, in this analysis, RPV appears to be benign from a lipid standpoint. In STARTMRK, RAL was also associated with a lesser effect on key lipid parameters compared with EFV. 25 So RAL is another drug that appears to have a benign lipid profile, particularly when it is combined with a NRTI backbone or compared with EFV. Also examined in STARTMRK were changes in appendicular limb fat. People who start on ARV therapy often gain weight from increases in appendicular fat, and they are protected against lipoatrophy. With backbones such as TDF or ABC with FTC or 3TC, we do not see limb fat loss, and when we switch people away from other drugs, we actually see limb fat recovery with these drugs. So, with a benign background, either EFV or RAL is not associated with the development of clinical lipoatrophy. Another study with lipid information was the SPIRAL study. 26 RAL was included in the initial therapy and was shown to be lipid benign. For patients taking LPV/r (which can affect lipids), the investigators found that if patients were switched to RAL, there was a substantial decline in triglycerides and total cholesterol. So, patients were getting lipid benefits as a result of switching, even in an unselected patient population. In the ROCKET 1 study, investigators specifically selected people who had a lipid abnormality. 27 To enter the study, patients needed to have a cholesterol value above 2 mg/dl (5.2 mmol/l). Individuals were randomized to continue on an ABC/3TC/EFV-based regimen, for 12 weeks, or to switch to the fixed dose formulation of TDF/FTC/EFV. So, patients were getting substitution from two pills to one, and finding out whether this change would improve lipid levels. At the end of 12 weeks, the group that had originally been randomized to continue on ABC/3TC was rolled over. It was found that switching from ABC/3TC to TDF /FTC resulted in substantial declines in total cholesterol. This switch resulted in many patients moving from a National Cholesterol Education Panel (NCEP) level where treatment might be appropriate, to a range were treatment would not be considered. An interesting finding in this study was that patients reported improved satisfaction with the treatment regimen when they moved from two pills to one pill per day. So, these findings support the idea that single tablet regimens are attractive to patients. 24. Cohen C, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. THLBB DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 21. Abst Martinez E, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. MOAB Moyle G, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. P8. 6

7 Another study of interest was the Rocket 2 study, which was conducted in Germany. 28 This study examined people who were on a boosted PI, but switched from ABC/3TC to TDF /FTC. Investigators saw changes of around 15% in total cholesterol. So, it is not a trick that we can do just on EFV; this is a switch that benefits people in both circumstances. In the ASSERT study, the primary endpoint was change in estimated glomerular filtration rate (egfr) using the Modification of Diet in Renal Disease (MDRD) method, comparing TDF/ FTC and ABC/3TC each with EFV. 29 The investigators reported no difference between the two groups. They did report that for tubular function markers, retinol binding protein leakage, or β2 microglobulin leakage, there was an effect with TDF that was predominantly observed during the first 24 to 48 weeks and then stabilized over time. There was probably some protein leakage for retinol binding protein, but it did not translate into anything meaningful from an egfr standpoint. When TDF was used as the switch agent in people with normal renal function in the ROCKET study, there was no change in renal function after making the switch. ACTG 5142 was another study that measured the adverse effects of treatment. 3 In this study, the investigators used NRTI-sparing and NRTI-containing regimens and patients who received NRTIs were treated with zidovudine (ZDV), stavudine (d4t) or TDF. Results from week 48 and 96 showed that a TDF-based regimen was associated with about a 1.5% greater reduction in bone mineral density (BMD) compared with the ZDV-based regimen (Figure 6). But the classic risk factors for low BMD were also relevant to BMD levels in this population: being female, post-menopausal, white and underweight were all risk factors for having a decline in BMD. Figure 6. ACTG 5142: Impact of Regimen on Change in Bone Mineral Density (BMD) at Week 48 and 96 3 % Change in BMD Week 48 Week 96 NRTI-sparing (n=195) d4t (n=92) ZDV (n=152) TDF (n=13) 28. Behrens G, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. WEPE Moyle G, et al. 12th ADRL; London, England; November 4-6, 21. Abst. O Huang J, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst. WEAB34. In study A5224s, the same phenomenon was observed: ABC and TDF were both associated with a decline in BMD at the lumbar spine. 31 However, the effect with TDF was about 1.5% greater, and that effect occurred largely in the first 24 weeks and then stabilized or regressed a bit over time. In the ASSERT study, we see the same phenomenon: BMD declining in both hip and spine areas. 32 The effect is more with TDF, but also true with ABC. What is interesting is that we see a recovery back towards baseline in the lumbar spine and any significant difference between the two groups disappearing, whereas for the total hip the difference of about 1.5% remains through 96 weeks, but is clearly stable from the 48 week time point onwards. Hyperbilirubinemia is often discussed as a side effect of ATV. However, there were interesting data presented on the idea that hyperbilirubinemia with ATV might be a good finding. In the CASTLE study, the frequency of hyperbilirubinemia (grade 3 and grade 4) at any point during the study was around 44%. 33 Mostly, it was around 2% of individuals. Only 3% of the subjects discontinued because of a clinically evident hyperbilirubinemia. Hyperbilirubinemia is linked to the plasma exposure of ATV. In the analysis of CASTLE, the investigators showed that if the patient has hyperbilirubinemia, he or she is more likely to be a treatment success. Something that we can potentially use in clinical practice is the idea that if we start somebody on ATV and we do not see a rise in hyperbilirubinemia, then we may need to start doing something about adherence or the plasma levels of ATV, or consider using a different drug, because hyperbilirubinemia is a signal that the patient has the appropriate exposure of ATV. Management Issues - Jürgen Rockstroh, MD The epidemiology of HIV infection was updated at IAC 21 in Vienna. Currently, 33.4 million people are living with HIV; of these, 4% know their status. 5 million are on therapy, 1 million are waiting for therapy. Clearly, a large number of patients do not know their diagnosis, which suggests the need for new testing strategies. There were 2 million deaths this year associated with HIV infection, and probably many of these could have been prevented if easy access to therapy was feasible. There were 2.7 million new infections, which does not suggest that prevention efforts overall are being successful. The majority of infections (22 million) are still in Sub-Saharan Africa, with some areas more affected than others. There are 1.2 million HIV-infected people in the United States, 2.3 million in Western Europe, 2 million in Latin America. Asia has rising numbers of infections as well. In Eastern Europe, 1.5 million are HIV-infected. 31. McComsey G, et al. 17th CROI; San Francisco, CA; February 16-19, 21. Abst. 16LB. 32. Moyle G, et al. 12th ADRL; London, England; November 4-6, 21. Abst. O Uy J, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. P93. 7

8 With regard to prevention, an exciting highlight in Vienna was the Center for the AIDS Program of Research in South Africa (CAPRISA) study, which investigated the effect of TDF gel for prevention of sexual transmission of HIV. 34 In this trial, women who were sexually active between the ages of 18 and 4 years and not using barrier contraception methods inserted TDF gel - one dose at 12 hours before sex and one at least 12 hours after sex, and no more than two doses within 24 hours. The study endpoints were HIV and herpes simplex infections. Although there was a more prominent effect in the earlier months of the trial, by month 3 there was a 39% reduction of sexual transmission of HIV in the study (Figure 7). The findings showed that TDF gel was effective for reducing the number of HIV infections. Figure 7. HIV Infections Over Time in the CAPRISA Study 34 Probability of Infection Months of Follow-up Effectiveness (P-value) 47% (.69) 5% (.7) 47% (.4) Placebo Tenofovir 4% (.13) P=.17 39% (.17) No TDF resistance was shown, tolerability was good and there was no evidence of systemic issues. Clearly, the concentration of TDF seemed to play a role in the study outcome - women who become HIV positive had lower cervical vaginal fluid concentration, suggesting that adherence issues or the time of application may play a role in preventing HIV infection. One of the important issues in HIV medicine is the impact of expanded HAART on new HIV diagnoses. Since the widespread use of HIV therapy in British Columbia, there has been a significant decline in new HIV diagnosis. 35 This is true even in the injecting drug users (IDU) community, which suggests that treatment is a potential strategy for reducing HIV infection. However, there are other signals of caution coming from work from China, which showed that in discordant couples, there were infections in the non- HIV-infected partner despite patients receiving HAART. 36 So not everyone achieves virological suppression, and transmission still can occur in discordant couples. Another important issue raised this year is malignancies in people with HIV infection. Data from the ART Cohort Collaboration shows that AIDS remains the leading cause of death (49.5%), because many patients come late into care, but of non-aids defining events that 34. Abdool Karim Q, et al. Science 21;329(5996): Montaner J, et al. Lancet 21:376(974): Ge Z, et al. 18th IAC; Vienna, Austria; July 18-23, 21. Abst THPDC12. cause death, it is non-aids defining malignancies that are leading the list (11.8%). 37 The overall increase in non-aids defining malignancies (NADM) is predominantly caused by an increase in anal cancer. 38 There has been progress in another issue, the treatment of HCV infection, in people with and without HIV co-infection. First, host genotypes were introduced as potential markers to identify patients with an increased probability of responding to treatments for HCV infection. It is important to keep in mind that the goal of HCV treatment is to cure, which is different from treatment for HIV. Researchers have identified the IL28B genotype as highly correlated with the probability that an individual will achieve sustained virological response (SVR) from HCV infection therapy. This applies to both HCV-only infected patients and those who have HIV and HCV co-infection. These findings have led researchers to speculate about the role this genetic marker may play in the future. Can it be used to identify patients who need shorter treatment durations? Can it be used as a prognostic marker to decide which patient should be treated now, because of the good outcome? Could this be a selection criteria for saying a patient will respond with interferon and RBV, so maybe he does not need potentially more costly treatments? It is worth noting that the serological course of a typical case of hepatitis C is characterized by potentially no symptoms in many patients during the initial phase of infection. By the time symptoms appear - usually liver enzyme increases, fatigue and potentially icterus - patients usually show positive HCV RNA, but the time until the immune system responds with the production of antibodies can take up to several months. So, if the suspicion is that the patient has an acute HCV infection, we should be prompted to think of doing HCV RNA testing. At the HIV1 meeting, recent statements from the Consensus Conference on Acute hepatitis C, which was organized by the NEAT network in Europe, were summarized. 39 They presented some very useful, pragmatic and clinically relevant algorithms. This has been an impressive year for new treatments. The biggest excitement was related to new drugs, especially telaprevir (TVR) and boceprevir (BOC). Unfortunately, because of some of the baseline characteristics of HIV/HCV co-infected patients - higher viral loads, additional therapies, possibility of drug-drug interactions - there has been some reluctance to study these new agents in co-infected populations. Although pilot trials with the new drugs have started, we have no data in co-infected patients at this point. Nevertheless, the presumed entrance of these new agents next year into our treatment options for HCV infection make it crucial to understand these results. These drugs will impact our treatment choices in co-infected individuals. 37. Gill, MJ, ART Cohort Collaboration, et al. Clin Infect Dis 21;5: Simard E, et al. Arch Intern Med 21;17: Vogel M, et al. HIV 1; Glasgow, Scotland; November 7-11, 21. Abst. O313. 8

9 The phase III studies of these new drugs for HCV were presented at the recent American Association for the Study of Liver Diseases (AASLD) meeting in Boston. One of the important studies was the ADVANCE trial, a phase III trial of TVR in combination with pegylated interferon/ribavirin (Peg/R) in HCV genotype 1 patients. 4 TVR was dosed either with Peg/R for 12 weeks and then a 12-week follow-up of Peg/R was provided, which was, depending on the patient s rapid early virologic response, either stopped or, if the HCV was still replicating, a longer period of therapy was provided. There was also a standard arm of Peg/R for 48 weeks and a shorter cycle of TVR of 8 weeks with Peg/R and then one month of placebo and Peg/R and then a continuing of Peg/R with RVR guidance. The data presented on the overall response rates showed that the addition of the TVR to Peg/R substantially increased the overall response rates to 75%. The response was a little bit lower in patients who received only 8 weeks of TVR, but even with the shorter period of TVR usage, there was a high response rate of 69%, compared with 44% in the Peg/R control arm. So, clearly, the benefit of the addition of this new medication becomes evident in this patient population. There were also impressive findings concerning BOC in the SPRINT trial. 41 This study involved genotype 1, HCV-treatment naïve patients. In this trial, there was a Peg/R lead-in for four weeks, and then either the continuation of Peg/R and placebo for 48 weeks or Peg/R + BOC for the remaining 44 weeks. There was also an arm that consisted of treatment with Peg/R until week 28, then if there was an undetectable HCV RNA in the treatment window of week 8 to 24, a shorter treatment duration, or if HCV RNA was detectable, a longer treatment duration was provided, again up to 48 weeks. There were two cohorts - one was non-black patients and the other was black patients. There were excellent overall response rates, with 67% in the response guided therapy in non-black patients and 68% with the shorter treatment duration at 48 weeks. Both of these were clearly higher than the 4% obtained in the Peg/R control. The response was somewhat lower in the black patients, although the response in the BOC arms was still significantly better than the Peg/R controls. If we consider the SVR rates in non-black patients in the modified Intent-to-Treat patients, for those with the short-term cycle of 28 weeks, in the response guided therapy, 7% responded, and 71% responded in the 48-week treatment group. These results suggest it is probable that the majority of patients who are treatment-naïve with HCV may be cured with this new therapy. Another issue in the treatment of HIV/HCV co-infected patients is that of drug-drug interactions. If we look at the metabolic pathways of different compounds and the studies that have been published, it becomes evident that there are quite a number of interactions to be considered not only the ones we already know that occur with 4. Jacobson IM, et al. 61st AASLD; Boston, MA; October 29-November 2, 21. Abst Poordad F, et al. 61st AASLD; Boston, MA; October 29-November 2, 21. Abst. LB-4 RBV and some of the NRTIs, but also with regard to PIs, NNRTIs, TVR and BOC, highlighting that we will need to be aware of these interactions to be sure that we do not decrease levels of the HCV PI. It is important to prevent sub-therapeutic drug levels, which may increase the risk of resistance development. At HIV1, there was one study looking at RBV and RAL, using a pharmacokinetics study. It was interesting because it showed that there was a lower Cmax, so there might be less toxicity. This is because Cmax can drive toxicity. However, the area under the curve (AUC) and Cmin were comparable, so there was good exposure and it is a good combination. RAL is not metabolized by the cytochrome P45 system, suggesting that it could be a very good drug in combination with TVR and BOC. 9