Treatmentupdate 220 Vol

TreatmentUpdate 220 Vol. 29, No. 2 · March/April 2017 Available online at www.catie.ca/en/treatmentupdate

I ANTI-HIV AGENTS Contents A. New drugs, new hope and I ANTI-HIV AGENTS possible timelines A. New drugs, new hope and At the recent Conference on Retroviruses and possible timelines 1 Opportunistic Infections (CROI), which took place in Seattle from February 13 to 16, 2017, researchers B. The capsid inhibitor—a new presented data about new anti-HIV compounds in class to enter clinical trials 2 development, including the following:

C. Bictegravir—an emerging • a new integrase inhibitor – bictegravir integrase inhibitor 3 • a new nuke (NRTI) – code-named GS-9131 • a non-nuke (NNRTI) – doravirine D. Bictegravir in the body— • a new protease inhibitor – code-named GS-PI1 preliminary information about • a capsid inhibitor (a new class of drug) – drug interactions 5 code-named GS-CA1

E. A new nuke in the works—GS-9131 6 As all of these drugs are in development, they do not yet have brand names and in some cases they F. Doravirine vs. darunavir 7 have only code names.

That these drugs are coming is good news for II MALE SEXUAL HEALTH people who have HIV that is resistant to some medications. However, as these are all new drugs A. Some issues related to sexual in development, they will take some time to come dysfunction in men 10 through the pipeline. B. Do integrase inhibitors affect testosterone levels in men? 13 Timelines The drugs that are closest to completing their final stages of clinical development are bictegravir and doravirine.

Bictegravir Results from the main phase III studies of the integrase inhibitor bictegravir should become produced by

555 Richmond Street West, Suite 505 Box 1104 Toronto, Ontario M5V 3B1 Canada phone: 416.203.7122 toll-free: 1.800.263.1638 fax: 416.203.8284 www.catie.ca charitable registration number: 13225 8740 RR Page 2 TreatmentUpdate 220 — Vol. 29 No. 2 ______available in the latter half of 2017. The drug’s were being developed as a standard formulation manufacturer, Gilead Sciences, will then submit a (immediate release). Gilead has to continue dossier about bictegravir to regulatory authorities experiments with the capsid inhibitor in animals, in Canada, the European Union and the U.S. and and if those go well, phase I studies in people then to other countries. It will probably take a should hopefully begin in 2018. year before regulatory agencies finish reviewing the data, which means that bictegravir is unlikely The experimental protease inhibitor, code-named to be approved until late summer or autumn of GS-PI1, appears to be furthest behind in the 2018. Once approved by Health Canada, bictegravir development timeline; clinical trials with this drug will have to undergo other secondary reviews and may not begin for several years. then Gilead will enter into negotiations with the provinces and territories about the drug’s price and In this issue of TreatmentUpdate we present its place on their formularies (lists of subsidized information that was made available at CROI medicines). Based on past trends, it is unlikely about these emerging therapies. that bictegravir will be listed on formularies until sometime in the first half of 2019.

Doravirine B. The capsid inhibitor—a new class to This non-nuke has completed most of the final enter clinical trials phase of clinical trials. The doravirine dossier will hopefully be submitted by the pharmaceutical Most approved anti-HIV drugs work by interfering company Merck to regulatory authorities in with an enzyme and/or protein that is needed by Canada, the European Union and the U.S. later this HIV-infected cells to make new viruses. year. Again, following past practices, it is likely that doravirine will not be approved until sometime in mid- to late 2018 and then it will probably take up A journey through the cell to a year to be subsequently listed on provincial and The capsid is the name given to the proteins territorial formularies. This means that doravirine that surround HIV’s genetic material. Upon HIV is not likely to be on these formularies until mid- attaching itself to a target cell of the immune to late 2019. system, the virus sends its genetic material (RNA) into the cell. As the genetic material is surrounded The other drugs by the capsid, it is protected from detection by the cell’s internal sensors. The capsid, along with its All of the other drugs previously mentioned are cargo of genetic material, then makes its way to the made by Gilead Sciences and are in very early stages cell’s control centre, or nucleus. Inside the nucleus of development. Although their development is the cell’s genetic material, which contains details have not been released, the nuke GS-9131 is instructions for the operation of the cell and helps likely to enter phase I clinical trials in 2017. Phase it carry out its functions. Once near the nucleus, I clinical trials assess the safety and preliminary the capsid releases its cargo, and through a series effectiveness of a drug. If the drug proves safe and of steps HIV’s genetic material is converted into a shows effectiveness, then it will move on to phase form similar to the cell’s genetic material (DNA). II. If all goes well, phase III trials could begin The capsid proteins then help HIV’s DNA cross within two to three years. into the nucleus, where it integrates into the cell’s DNA. At some point in the future, perhaps through The capsid inhibitor (GS-CA1) is the most immunological stimulation, the cell becomes interesting of the new compounds because it activated and HIV’s DNA takes over the cell and is the first drug of its kind to be developed. In converts it into a mini-virus factory, producing new experiments Gilead scientists noticed that the copies of HIV. capsid inhibitor breaks down slowly. As a result, a long-acting formulation of the capsid inhibitor has been created. As no long-acting formulation of any anti-HIV drug has been approved, the development of the capsid inhibitor may take longer than if it Page 2 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 3

More about the capsid In a phase II randomized clinical trial, researchers gave 131 people who had not previously used HIV The capsid has several functions, as follows: therapy bictegravir or dolutegravir, each drug taken with a backbone of TAF (tenofovir alafenamide) • it protects HIV’s genetic material and FTC (emtricitabine). Both bictegravir- and • it helps HIV’s genetic material gain entry to dolutegravir-containing regimens performed well the nucleus of a cell over 48 weeks, with more than 90% of participants • it helps the new copies of HIV become achieving a viral load less than 50 copies/mL. Side infectious effects were common but were mostly mild or moderate. No side effects were graded as serious Thus, a capsid inhibitor could work by interrupting and no one died in the study. or impairing three different parts of HIV’s life cycle. In theory, since the capsid inhibitor has so Bictegravir, which will be co-formulated (put into many anti-HIV activities, it could be used by itself one pill) with TAF and FTC, can be taken once in the prevention of HIV infection. However, daily. Phase III clinical trials are underway with much work lies ahead before this drug’s developer, the bictegravir-containing combination and results Gilead Sciences, can be certain about that. A long- should be available in the second half of 2017. A acting formulation of the capsid inhibitor has trial with about 470 HIV-positive women using a been developed and can maintain high levels in bictegravir-containing regimen is planned for later dogs for at least 10 weeks. This finding suggests that in 2017. the capsid inhibitor has potential for intermittent dosing in people—perhaps every one or two months. However, this formulation likely will need Study details further testing in animals, particularly in monkeys susceptible to SIV (simian immunodeficiency virus, Researchers in the U.S. randomly assigned which is closely related to HIV), before human participants in a 2:1 ratio to receive the following: studies begin. Taking all of this information into account, clinical trials with the capsid inhibitor • bictegravir (75 mg) + TAF + FTC – may not begin until 2018. 65 participants • dolutegravir + TAF + FTC – 33 participants

REFERENCE: Participants could take the study medicines with Tse WC, Link JO, Mulato A, et al. Discovery of novel potent or without food, once daily. Several doses of HIV capsid inhibitors with long-acting potential. Conference bictegravir have been assessed in earlier studies and on Retroviruses and Opportunistic Infections, 13-16 February 2017, as a result of these studies Gilead scientists have Seattle. Abstract 33. decided that the 75-mg daily dose is best.

The average profile of participants in the study was C. Bictegravir—an emerging as follows: integrase inhibitor • men – 96%, women – 4% Bictegravir (formerly GS-9883) is a potent integrase • age – 31 years inhibitor under development for the treatment • 94% of participants were free from symptoms of people with HIV. Bictegravir is made by related to HIV disease Gilead Sciences. • viral load – 25,000 copies/mL • CD4+ count – 444 cells/mm3 In laboratory experiments with cells and HIV, • estimated glomerular filtration rate (eGFR; a bictegravir can work against many strains of HIV measure of kidney health) – 125 mL/minute that are resistant to other integrase inhibitors, such as raltegravir (Isentress) and elvitegravir (in The study lasted for 48 weeks. Genvoya and Stribild). Bictegravir is also effective against some strains of HIV that are resistant to another integrase inhibitor, dolutegravir (Tivicay and in Triumeq). Page 4 TreatmentUpdate 220 — Vol. 29 No. 2 ______

Results—Changes in viral load Changes in CD4+ cell counts Regimens based on integrase inhibitors can quickly On average, participants taking bictegravir had drive down viral load in the blood and the drugs 258 more CD4+ cells by the end of the study and used in this study were no exception. dolutegravir users had 192 more CD4+ cells. This difference was not statistically significant. Week 12 By the 12th week of the study, 94% of all participants had a viral load less than 50 copies/mL in their Side effects blood samples. Overall, side effects were distributed as follows:

Week 24 • bictegravir-based regimen – 85% developed By the 24th week of the study, small differences side effects in the proportion of participants who were • dolutegravir-based regimen – 65% developed virologically suppressed emerged as follows: side effects

• bictegravir-based regimen – 97% had a viral The distribution of specific side effects was load less than 50 copies/mL as follows: • dolutegravir-based regimen – 94% had a viral load less than 50 copies/mL Diarrhea • bictegravir-based regimen – 12% Week 48 • dolutegravir-based regimen – 12% By the 48th week of the study, the distribution of participants with suppressed viral loads was Nausea as follows: • bictegravir-based regimen – 8% • dolutegravir-based regimen – 12% • bictegravir-based regimen – 97% had a viral load less than 50 copies/mL Bone pain • dolutegravir-based regimen – 91% had a viral • bictegravir-based regimen – 6% load less than 50 copies/mL • dolutegravir-based regimen – 6%

None of these differences in viral loads was Fatigue statistically significant. • bictegravir-based regimen – 6% • dolutegravir-based regimen – 6% A closer look Using a more sensitive viral load assay with a Liver enzymes lower limit of 20 copies/mL, the distribution of In general, neither regimen was associated with any suppressed viral loads at week 48 was as follows: signals of toxicity to major organ-systems. However, temporarily elevated liver enzyme (ALT, AST) levels • bictegravir-based regimen – 91% had a viral in the blood seemed more likely to occur among a load less than 20 copies/mL minority of bictegravir users—between 6% (ALT) • dolutegravir-based regimen – 88% had a viral and 9% (AST). The reasons for this are not clear. load less than 20 copies/mL In one case the researchers underscored that a participant had recently become infected with This difference in viral loads was not statistically hepatitis C virus and also drank excessive amounts significant. of alcohol. Both of these factors cause liver injury and inflammation and would increase liver enzyme According to the study team, adherence among a levels in the blood. As for all the other participants minority of dolutegravir users was less than ideal. with temporarily elevated liver enzymes, as this This may have affected the results. was a relatively small study, some of those findings could have occurred by chance. Page 4 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 5 Creatine kinase D. Bictegravir in the body— Elevated levels of the enzyme creatine kinase (also preliminary information about called creatine phosphokinase) were found in drug interactions the blood of 13% of participants who were taking bictegravir and 9% of those taking dolutegravir. Bictegravir (formerly GS-9883) is an experimental These elevations were temporary. integrase inhibitor being developed by Gilead Sciences and is currently in phase III clinical trials. Elevated levels of these enzymes can occur in cases Below is some preliminary information about of muscle inflammation and injury. For example, if the drug. a blood sample was drawn after lifting weights or engaging in resistance exercises, levels of creatine It is powerful and active against many strains of kinase would be temporarily elevated. Other HIV that are resistant to the following integrase researchers have documented persistently elevated inhibitors: creatine kinase levels in a very small proportion of patients who were experiencing muscle injury • elvitegravir (in Genvoya and Stribild) arising as a side effect of the integrase inhibitor • raltegravir (Isentress) raltegravir (Isentress). However, in the present clinical trial, researchers did not think that the Bictegravir is also effective against some strains of temporarily increased levels of creatine kinase were HIV that are resistant to the integrase inhibitor a consequence of drug side effects from bictegravir dolutegravir (Tivicay and in Triumeq). or dolutegravir, which have chemical structures somewhat similar to raltegravir. A single 75-mg dose of bictegravir is sufficient to maintain levels of this drug in the blood so that once-daily dosing is sufficient. Bear in mind Bictegravir is well absorbed and is slowly broken This is a small phase II clinical trial. As a result, firm down by these enzymes in the body—CYP3A4 conclusions about which regimen is better cannot and UGT1A1. be drawn. Phase II studies are designed to find preliminary evidence of safety and effectiveness After bictegravir is licensed, the manufacturer that can then be explored in a trial of a more robust will release instructions about how it should be statistical design, such as a randomized phase III used, along with information about potential and study. Phase III clinical trials are underway to actual drug interactions. In the meantime, here is assess bictegravir’s potential against dolutegravir some preliminary information about some drug and other anti-HIV drugs. The results from these interactions with bictegravir. studies should become available in the latter half of 2017. Bictegravir is also being tested in treatment- experienced patients and a trial to better assess Acid-reducing agents, laxatives, metal bictegravir’s safety in women is being considered supplements and buffered medicines by Gilead. Gilead Sciences recommends that bictegravir be taken 2 hours before or 2 hours after taking the REFERENCES: following medicines. 1. Sax PE, DeJesus E, Crofoot G, et al. Randomized trial of bictegravir or dolutegravir with FTC/TAF for initial HIV Acid-reducing agents, including the following: therapy. Conference on Retroviruses and Opportunistic Infections. 13-16 February 2017, Seattle. Abstract 41. • Alka-Seltzer 2. Lee FJ, Amin J, Bloch M et al. Skeletal muscle toxicity Gaviscon (tablets and syrup) associated with raltegravir-based combination antiretroviral • therapy in HIV-infected adults. Journal of Acquired Immune • Maalox (liquid and tablets) Deficiency Syndromes. 2013 Apr 15;62(5):525-33. • Milk of Magnesia 3. Calza L, Danese I, Colangeli V, et al. Skeletal muscle • Pepto-Bismol and Pepto Bismol Childen’s toxicity in HIV-1-infected patients treated with a raltegravir- • Rolaids containing antiretroviral therapy: a cohort study. AIDS • Tums Research and Human Retroviruses. 2014 Dec;30(12):1162-9. Page 6 TreatmentUpdate 220 — Vol. 29 No. 2 ______

Metal supplements including those containing All three drugs in one pill will provide a complete iron, calcium and magnesium should also follow treatment option. the same two hour guidance. Tests have shown that all three drugs are well Antibiotics absorbed when taken together. When all three Drugs such as rifabutin and rifampin speed up drugs are taken with food, the absorption of the activity of the enzymes CYP3A4 and UGT1A1. bictegravir increases by about 24%. This is not Taking these drugs can reduce the amount of seen as clinically significant and so the company bictegravir in the blood between 38% (in the case recommends that all three drugs can be taken with of rifabutin) and 75% (in the case of rifampin). or without food.

Antifungal drugs REFERENCE: The drug voriconazole (Vfend) impairs the activity of the enzyme CYP3A4 and raises bictegravir Zhang H, Custudio JM, Wei X, et al. Clinical pharmacology of the unboosted integrase strand transfer inhibitor bictegravir. concentrations by 61%. Randomized trial of bictegravir or dolutegravir with FTC/ TAF for initial HIV therapy. Conference on Retroviruses and Diabetes drugs Opportunistic Infections. 13-16 February 2017, Seattle. Abstract 40. Metformin (Glucophage) is commonly prescribed by doctors as part of a plan to help control blood sugar. Bictegravir can increase levels of metformin in the blood by almost 40%. This could lead to side E. A new nuke in the works—GS-9131 effects such as nausea and diarrhea in some people who use metformin. It is likely that doctors may Gilead Sciences is developing a new nucleoside have to reduce the dose of metformin in bictegravir analogue (nuke) code-named GS-9131. Once inside users. A similar issue occurs with the use of another of cells, GS-9131 becomes activated by enzymes integrase inhibitor, dolutegravir, and metformin. and turns into a compound with anti-HIV activity called GS-9148. Drugs that are taken in one form Hepatitis C drugs and then converted into another form once in the Bictegravir does not affect the concentrations of body are called pro-drugs. So far research suggests the drugs (ledipasvir and sofosbuvir) that are co- that GS-9131 (or GS-9148) is not likely to accumulate formulated and sold as Harvoni. Gilead has not in kidney cells or harm the parts of the cell that released information about potential interactions generate power (mitochondria). This is important between bictegravir and hepatitis C medicines because older nukes tended to injure mitochondria made by other companies. and cause problems for users. Also, an earlier version of the nuke tenofovir DF (tenofovir disoproxil HIV protease inhibitors fumarate) tended to accumulate in the kidneys of The drug atazanavir (Reyataz) inhibits the activity some patients and cause kidney dysfunction. of CYP3A4 and UGT1A1 and can therefore significantly raise bictegravir levels by 310%. For the rest of this brief report we will refer only to GS-9131 for the sake of simplicity. Hormones Bictegravir does not affect levels of commonly Activity against HIV used forms of estrogen (norgestimate and ethinyl estradiol) that are in contraceptive pills. There are two main strains of HIV as follows:

• HIV-1 – the most common strain A treatment in one pill • HIV-2 – a less common strain found mostly in Bictegravir will be co-formulated with the parts of West Africa following two other drugs: HIV-1 can be further subdivided into many subtypes • TAF (tenofovir alafenamide; the new, safer such as A, B, C, D and so on. Subtype B is most version of tenofovir) commonly found in North America, Central and • FTC (emtricitabine) South America, Western Europe, Japan, Australia Page 6 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 7

and New Zealand. In lab studies with cells and Doravirine can be dosed once daily with or without HIV, GS-9131 is active against many subtypes of HIV. food. In addition to being developed in a 100-mg pill, doravirine is also being developed as a fixed- GS-9131 is also active against some strains of dose formulation with the following two drugs: HIV that have arisen because of resistance to the following nukes: • tenofovir DF (Viread and in Truvada and many other combinations) • abacavir (Ziagen and in Kivexa and Trizivir) • 3TC (lamivudine and in Triumeq and many • emtricitabine (FTC and in Truvada and many other combinations) other combinations) • ddI (Videx) Merck, the developer of doravirine, recently • AZT (Retrovir and in Combivir and Trizivir) conducted a randomized, placebo-controlled • d4T (Zerit) study comparing regimens based on doravirine • tenofovir DF (Viread and in Truvada and to regimens based on darunavir (Prezista and many other combinations) Prezcobix). Darunavir is the leading protease inhibitor used in high-income countries today. GS-9131 has increased antiviral activity against HIV It has to be taken with a small dose of another when it is combined with the following drugs: drug, ritonavir (Norvir), which helps to boost or maintain levels of darunavir in the blood so • TAF (tenofovir alafenamide; the new, safer that it can be taken only once daily. In its clinical formulation of tenofovir) trial Merck found that doravirine was roughly • tenofovir DF equivalent in potency to darunavir-based regimens. • abacavir • efavirenz (Sustiva, Stocrin and in Atripla) • nevirapine Study details • darunavir (Prezista and in Prezcobix) Upon entering the study the average profile of • dolutegravir (Tivicay and in Triumeq) participants was as follows: • bictegravir • no participants had previously used HIV Thus, GS-9131 may be useful as part of regimens drugs and no participants were infected for people who have strains of drug-resistant HIV. with HIV that was resistant to doravirine Initial clinical trials of this drug should begin or darunavir in 2017. • age – 35 years • 84% men, 16% women REFERENCE: • 10% had symptoms of AIDS in the past 70% had the strain of HIV that is most White K, Margot N, Stray K, et al. GS-9131 is a novel NRTI • with activity against NRTI-resistant HIV-1. Conference on common in North America and Western Retroviruses and Opportunistic Infections, 13-16 February 2017, Europe – subtype B Seattle. Abstract 436. • viral load – 25,000 copies/mL • 20% of participants had a viral load greater than 100,000 copies/mL • CD4+ count – 422 cells/mm3 F. Doravirine vs. darunavir • 14% of participants had a CD4+ count of 200 cells/mm3 or less Doravirine is an experimental non-nuke that is undergoing phase III clinical trials. It is designed The nukes used in this study were as follows: to be effective against most strains of HIV that are resistant to other non-nukes, such as the following: • tenofovir DF + FTC • abacavir + 3TC • efavirenz (Sustiva, Stocrin and in Atripla) • nevirapine • rilpivirine (Edurant and in Complera) Page 8 TreatmentUpdate 220 — Vol. 29 No. 2 ______

Data were released on study participants after one Among participants who entered the study year. Their distribution was as follows: with a CD4+ count of 50 or less cells/mm3, the proportions with a suppressed viral load at week • doravirine-based regimen – 327 people 48 were as follows: • darunavir-based regimen – 312 people • doravirine-based regimens – 83% The study will continue for two years. • darunavir-based regimens – 67%

CD4+ cell counts increased over the course of the Results—Changes in viral load and study. Below are the average increases in e cell CD4+ cell counts counts for each regimen by week 48: Overall, after one year, the proportions of doravirine-based regimens – 193 cells/mm3 participants who had a viral load less than 50 • darunavir-based regimens – 186 cells/mm3 copies/mL were distributed as follows: • This difference in CD4+ cell counts was not • doravirine-based regimens – 84% statistically significant. • darunavir-based regimens – 80%

Statistical analysis found that both regimens are Side effects roughly equivalent (the technical term for this is non-inferior). About 30% of all participants experienced side effects; this is relatively common when people The following proportions of participants were begin HIV treatment in or out of clinical trials. unable to keep their viral load suppressed: In most cases, side effects should fade after a few weeks. However, 2% of participants on doravirine • doravirine-based regimens – 11% and 3% on darunavir had to quit the study due to • darunavir-based regimens – 13% side effects.

Data from the remaining participants was not Common side effects were distributed as follows: yet available. Diarrhea Among participants who entered the study with • doravirine-based regimens – 14% a viral load greater than 100,000 copies/mL, the • darunavir-based regimens – 22% proportions with a suppressed viral load at week 48 were as follows: Nausea • doravirine-based regimens – 11% • doravirine-based regimens – 81% • darunavir-based regimens – 12% • darunavir-based regimens – 76% Headache Among participants who entered the study with • doravirine-based regimens – 11% a CD4+ count greater than 200 cells/mm3, the • darunavir-based regimens – 14% proportions that were virologically suppressed at week 48 were as follows: Rash • doravirine-based regimens – 7% • doravirine-based regimens – 89% • darunavir-based regimens – 8% • darunavir-based regimens – 89%

Among participants who entered the study with Focus on the brain 3 a CD4+ count between 51 and 200 cells/mm , the All non-nukes are based on a chemical structure proportions with a suppressed viral load at week 48 distantly related to Valium-type drugs. This means were as follows: that they can get inside the brain, which is a sanctuary for HIV. However, it also means non- • doravirine-based regimens – 83% nukes have the potential to cause brain-related side • darunavir-based regimens – 74% Page 8 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 9

effects (also called neuropsychiatric side effects). As Creatinine (used to assess kidney health) an example, efavirenz was a first-generation non- • doravirine-based regimens – 1% nuke that is notorious for causing brain-related • darunavir-based regimens – 3% side effects. Examples of brain-related side effects include the following: Creatine kinase (sometimes called creatinine phosphokinase) • concentration problems Elevated levels of creatine kinase indicate that • confusion muscle inflammation and injury may be occurring. • dizziness However, given the low levels of this issue found in • difficulty falling asleep and/or staying asleep this study (regardless of the regimen used) and that • vivid dreams there were no complaints about muscle pain, it is • in rare cases depressive illness unlikely that this was a problem.

We do not have detailed information about brain- • doravirine-based regimens – 2% related side effects from this study. • darunavir-based regimens – 2%

The overall distribution of brain-related side effects was as follows: More about cholesterol and triglycerides Over the long-term, elevated levels of LDL-C are • doravirine-based regimens – 11% associated with an increased risk for cardiovascular • darunavir-based regimens – 13% disease. In the present study, when analyses were done on blood samples for their lipid No participant left the study because of these (cholesterol and triglyceride) levels, researchers side effects. asked participants to fast before the samples were collected. As a result of deeper analysis of lipid levels, researchers found that there was a small Abnormal lab test results but significant increase in LDL-C levels among Analysis of blood samples from participants participants taking darunavir. In contrast LDL-C detected few severe abnormalities. If abnormal levels fell modestly in doravirine users. Triglycerides test results did occur, for the most part they were also rose among darunavir users but declined in generally of mild to moderate intensity. doravirine users.

Here is the distribution of severely abnormal Levels of HDL-C (“good cholesterol”) rose elevated blood test results: modestly in participants regardless of which study drug they used. LDL-C (“bad cholesterol”) • doravirine-based regimens – less than 1% • darunavir-based regimens – 3% Summary Overall, the study shows that doravirine is not Blood sugar inferior to darunavir and is a potent and highly • doravirine-based regimens – 1% effective treatment, particularly for people who are • darunavir-based regimens – less than 1% initiating HIV therapy, with only some participants experiencing side effects. AST (a liver enzyme) • doravirine-based regimens – 1% • darunavir-based regimens – 3% REFERENCE: Molina J-M, Squires K, Sax P, et al. Doravirine is non-inferior ALT (a liver enzyme) to darunavir + ritonavir in a phase 3 treatment-naïve trial at • doravirine-based regimens – 1% week 48. Conference on Retroviruses and Opportunistic Infections. 13-16 February 2017, Seattle. Abstract 45 LB. • darunavir-based regimens – 2% Page 10 TreatmentUpdate 220 — Vol. 29 No. 2 ______II MALE SEXUAL HEALTH patient about it. This may lead to an investigation by the doctor and/or referral to a specialist such as a urologist, endocrinologist, psychologist, A. Some issues related to sexual psychiatrist or others as needed. dysfunction in men

Thanks to the power of modern HIV treatment Key risk factors for ED (ART) many HIV-positive people in Canada and ED occurs in HIV-negative men and the same risk other high-income countries who are aware of their factors that operate in that population may also status and engaged in their care and treatment and affect HIV-positive men or may be accentuated in who do not have serious co-infections, unmanaged them. Below are some possible risk factors for ED. mental health conditions or addiction, are expected by researchers to have a near-normal life expectancy. Smoking ART also has another great effect: By suppressing This is a well-established risk factor for ED. HIV to levels so low that they are undetectable with routine lab tests, and when people continue Low testosterone levels to take ART every day so that their viral load stays HIV infection can reduce levels of testosterone and undetectable, studies have found that HIV-positive other hormones. A key part of ruling out lower- people do not pass on the virus to their sexual than-normal levels of testosterone as a cause of ED partners. Given these twin benefits of ART, a healthy is a blood test for this hormone. sex life contributes to good quality of life and from time to time sexual dysfunction can be a problem Note that there are antibodies in the blood that for some men living with HIV. In general, there is bind to testosterone. Only the testosterone that is less research on female sexual dysfunction and far unbound is available for use by the body’s cells. This less on such dysfunction in women with HIV. unbound testosterone is called “free testosterone.” Thus, when getting testosterone measured, In this issue of TreatmentUpdate we review key specialists often request that free testosterone be ideas about male sexual dysfunction. assessed by laboratories.

Erectile dysfunction Studies have found that HIV-positive men, whether or not they are using ART, tend to have lower-than- The inability to get and maintain a firm erection normal levels of testosterone (a condition called is called erectile dysfunction (ED). This is one hypogonadism). This may be caused by HIV directly of the more common problems that all men as HIV-infected cells produce compounds that may can experience. injure the testicles (a major source of testosterone), or it may be caused indirectly through the ongoing It is difficult to be certain how common ED is inflammation that is associated with HIV disease. among HIV-positive men because many studies that have collected data about ED did not focus on Abnormal lipid levels this issue and explore it. Despite this shortcoming, Cholesterol and triglycerides are fatty substances studies suggest that between 50% and 60% of HIV- (lipids) in the blood. Abnormal concentrations positive men who were surveyed disclosed that of these are associated with an increased risk for they have experienced ED. As ED can be a difficult cardiovascular disease. Prolonged abnormal levels subject to talk about, it is possible that more of lipids in association with ED suggests the men have ED than have disclosed this problem possibility that problems with blood circulation in surveys. are developing and possibly affecting the flow of blood to and retention of blood within the penis. There are many factors that can underpin ED— sometimes there may be biological reasons, other Type 2 diabetes times there may be psychological reasons, and ED is common in males with type 2 diabetes likely still other times there may be a combination of because diabetes can affect circulation of blood and these two areas that underpin ED. Whatever the is associated with nerve injury. cause of ED in an individual, diagnosis should usually prompt a discussion between doctor and Page 10 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 11

Elevated blood pressure if the medicines that you are using are on this list of It is normal to have higher-than-normal blood drug classes. Note that there might be drugs/classes pressure while exercising or during stressful that are not listed that may also be linked to ED and periods. However, prolonged higher-than-normal this is yet another reason why conversations with blood pressure can injure blood vessels and organs. pharmacists (in addition to doctors) are important Elevated blood pressure is a risk factor for ED. when investigating drug side effects.

Circulatory issues • anabolic steroids Good flow of blood is necessary to achieve an • anti-anxiety medicines erection. Not only must blood flow into the penis, • some antidepressants it must stay there for the duration of sex. However, • some antacids called histamine-2 antagonists in cases where blood vessels are partially blocked • some antiseizure drugs due to cardiovascular disease, ED can occur. Injury • drugs to reduce high blood pressure to the penis from trauma can also affect the • calcium channel blockers circulation of blood in that area. • some diuretics (thiazides and spironolactone) • hormones – estrogens and corticosteroids Obesity • recreational drugs – alcohol, cocaine, This is another well-established risk factor for ED. marijuana, methamphetamine

Psoriasis Emerging research suggests the possibility that ART some men who have psoriasis may be at increased There is no firm evidence that ART causes ED. risk for ED. This issue is explored in the following report in this issue of TreatmentUpdate. However, Italian Psychological issues doctors who study HIV and ED have suggested that Factors affecting mental health can affect sexual doctors treating HIV-positive patients consider the health and functioning. For instance, anxiety and possibility of changing a person’s HIV treatment if depression can also contribute to ED. “ED appeared soon after starting [this treatment].” Unfortunately, HIV is still a stigmatized condition and some HIV-positive men may worry about Screening and treatment of ED inadvertently passing on the virus to their sexual partners. This and other worries can contribute The Italian doctors also recommended that HIV- to ED. Also, doctors have generally found that positive men receive counselling to help them even if ED was ultimately triggered by biological reduce modifiable risk factors they may have that factors, the presence of ED can then incite the are contributing to ED. Such factors could include development of psychological issues that play a the following: role in prolonging ED. • cigarette smoking Some men may also experience feelings of no • insufficient exercise longer feeling sexually desirable. • obesity • alcohol and/or other substance use In cases where there is a psychological component underpinning ED, referral to a therapist may A next step is to include assessments to uncover be useful. underlying biological and hormonal risk factors (including diabetes, reduced testosterone levels, abnormal lipid levels in the blood, and so on). If Medicines such problems are found, treating them can help improve overall health and quality of life and Some classes of medicines may increase the risk of perhaps ED. ED and some even cause problems with orgasm and/or ejaculation. The following classes of drugs have been associated with ED in some men. A review with your pharmacist can help you identify Page 12 TreatmentUpdate 220 — Vol. 29 No. 2 ______

The most common drugs to treat ED are inhibitors improve the overall health of HIV-positive people of an enzyme called PDE-5 and include the and may have an impact on reducing the risk of ED following: in some HIV-positive men.

• Cialis • Levitra Sexual dysfunction • Viagra In addition to ED there are other forms of sexual dysfunction that can occur in men, such as reduced One of these will usually work for ED. However, sexual desire or interest in sex. These problems can in cases where these drugs do not work, referral occur because of anxiety, depression, relationship to a urologist for further investigation can be a difficulties and other issues. Loss of interest in sex useful next step. Note that these drugs can interact can occur because of reduced testosterone levels. with some medicines and recreational substances, Some people, for many reasons, may no longer so a discussion with your doctor and pharmacist feel desirable. about possible interactions and side effects of ED treatment is necessary. Thus, in some cases, much investigation by family doctors and/or other specialists may be required to unravel and understand possible factors underlying A note about diet sexual dysfunction and how to deal with them. Observational studies suggest that diet can play This requires time and patience. a role in reducing the risk of developing ED in HIV-negative men. A longitudinal U.S. study that More research is needed to understand sexual collected data between the years 2000 and 2008 on dysfunction in HIV-positive men and ways to more than 25,000 men found that those who ate remedy this issue. diets high in certain fruits (including strawberries, blueberries, apples, pears and citrus) had a 14% REFERENCES: reduced risk for developing ED compared to men who did not eat such a diet. These fruits 1. Santi D, Brigante G, Zona S, et al. Male sexual dysfunction and HIV—a clinical perspective. Nature Reviews Urology. 2014 contain naturally occurring compounds that act as Feb;11(2):99-109. antioxidants and can help to reduce inflammation. When researchers focused on fruits with the 2. McVary KT. Sexual dysfunction. In: Kasper, Fauci, Hauser, Longo, Jameson, Loscalzo, editors. Harrison’s Principles of highest amount of these compounds—citrus Internal Medicine. 19th Edition. 2015. McGraw-Hill Education. and blueberries—the risk of developing ED was Pages 324-330. reduced by 19%. These effects were most likely in 3. Lachâtre M, Pasquet A, Ajana F, et al. HIV and men who were less than 70 years old. These findings hypogonadism: a new challenge for young-aged and middle- should not be misinterpreted to mean that citrus aged men on effective antiretroviral therapy. AIDS. 2017 Jan and blueberries can stop ED or are of equivalent 28;31(3):451-453. potency to ED treatments. Instead, these colourful 4. Wunder DM, Bersinger NA, Fux CA, et al. Hypogonadism fruits seem to help reduce the risk for developing in HIV-1-infected men is common and does not resolve during ED. They are not a substitute for engaging in other antiretroviral therapy. Antiviral Therapy. 2007;12(2):261-5. aspects of healthy living (such as quitting smoking, 5. Collazos J, Esteban M. Has prolactin a role in the losing weight, engaging in daily exercise and so on). hypogonadal status of HIV-infected patients? Journal of the International Association of Physicians in AIDS Care. 2009 Jan- Feb;8(1):43-6. A much smaller observational study in 65 men, 6. Lamers SL, Rose R, Maidji E, et al. HIV DNA Is frequently half of whom ate a Mediterranean-type diet (rich present within pathologic tissues evaluated at autopsy in whole grains, fruit, vegetables, nuts, legumes from combined antiretroviral therapy-treated patients and olive oil) found that those on the diet were with undetectable viral loads. Journal of Virology. 2016 Sep less likely to develop ED. Such diets have been 29;90(20):8968-83. known to reduce the risk of type 2 diabetes and 7. Jenabian MA, Costiniuk CT, Mehraj V, et al. Immune cardiovascular disease; that they might have related tolerance properties of the testicular tissue as a viral sanctuary benefits (such as on ED) is not surprising. site in ART-treated HIV-infected adults. AIDS. 2016 Nov 28;30(18):2777-2786. Since diets high in colourful fruits and vegetables 8. Slama L, Jacobson LP, Li X, et al. Longitudinal changes have generally beneficial effects, they should also over 10 years in free testosterone among HIV-infected and Page 12 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 13

HIV-uninfected men. Journal of Acquired Immune Deficiency • HIV-related inflammation and injury to the Syndromes. 2016 Jan 1;71(1):57-64. body’s hormonal networks 9. De Ryck I, Van Laeken D, et al. Erectile dysfunction, • the development of life-threatening infections testosterone deficiency, and risk of coronary heart disease in and prolonged and intense regimens of a cohort of men living with HIV in Belgium. Journal of Sexual Medicine. 2013 Jul;10(7):1816-22. antibiotics, antifungals and antivirals needed to treat and later prevent infections 10. Biebel MG, Burnett AL, Sadeghi-Nejad H. Male sexual from recurring function and smoking. Sexual Medicine Reviews. 2016 Oct;4(4):366-375. However, lower-than-normal levels of testosterone 11. Egeberg A, Hansen PR, Gislason GH, et al. Erectile dysfunction in male adults with atopic dermatitis and also have been found among HIV-positive men in psoriasis. Journal of Sexual Medicine. 2017; in press. the subsequent era who were using ART and never 12. Omland T, Randby A, Hrubos-Strøm H, et al. Relation developed AIDS. of erectile dysfunction to subclinical myocardial injury. American Journal of Cardiology. 2016 Dec 15;118(12):1821-1825. The reasons for this are not clear but may be related 13. Cassidy A, Franz M, Rimm EB. Dietary flavonoid intake to dysfunction in the body’s production of some and incidence of erectile dysfunction. American Journal of hormones, including testosterone, perhaps arising Clinical Nutrition. 2016 Feb;103(2):534-41. directly or indirectly from HIV infection. 14. Esposito K, Ciotola M, Giugliano F, et al. Mediterranean diet improves erectile function in subjects with the metabolic Decreased testosterone levels have also been linked syndrome. International Journal of Impotence Research. 2006 to the following: Jul-Aug;18(4):405-10. 15. Boddi V, Fanni E, Castellini G, et al. Conflicts within • excessive intake of alcohol the family and within the couple as contextual factors in the injecting street drugs determinism of male sexual dysfunction. Journal of Sexual • Medicine. 2015 Dec;12(12):2425-35. • hepatitis C virus infection 16. Chou NH, Huang YJ, Jiann BP. The Impact of illicit use of amphetamine on male sexual functions. Journal of Sexual Medicine. 2015 Aug;12(8):1694-702. Measuring testosterone There are antibodies in the blood that bind to hormones such as testosterone. The unbound (or “free”) testosterone is what is available for use by the B. Do integrase inhibitors affect body’s cells. Therefore, when assessing testosterone testosterone levels in men? levels, endocrinologists usually ask the laboratory to measure the amount of free testosterone in Lower-than-normal levels of testosterone in men the blood. Hormone levels in the body usually are associated with the following problems: vary by time of day (because of internal 24-hour cellular clocks). Researchers who study testosterone • decreased interest in sex recommend that measurements of free testosterone • erectile dysfunction be done early in the morning. • reduced muscle mass and strength • thinning bones Researchers in Paris and elsewhere in France have • fatigue conducted a study with 113 HIV-positive men, all • in some cases, depression less than 50 years old, who did not have AIDS and who were taking ART and who had a viral load less Decreased testosterone levels occur as all men age. than 50 copies/mL. The researchers published their findings in the January 28, 2017 issue of the journal In the time before potent HIV treatment AIDS. They found that about 12% of the men had (ART) became available, researchers found low lower-than-normal levels of testosterone (measured testosterone levels in some men with HIV. In such as free testosterone)—less than 70 pg/mL. This cases this problem may have arisen for several rate of low testosterone (called hypogonadism) is reasons, including the following: double the rate that would be seen in HIV-negative men of a similar range in age. • unintentional and severe weight loss (due to HIV disease) The researchers stated that they found a link between the use of integrase inhibitors and the Page 14 TreatmentUpdate 220 — Vol. 29 No. 2 ______presence of low testosterone. We caution readers factors, including the nature of the study, which is that due to the study’s design and other issues, explained below. such a conclusion must be treated very cautiously, and we explain why the researchers may have inadvertently arrived at such a conclusion. Bear in mind 1. This study’s design is cross-sectional in nature; data were captured largely at one Study details point in time. Cross-sectional studies are The average profile of the men when they were good at finding associations between a drug recruited for this study was as follows: and, in this case, a problem (hypogonadism). However, cross-sectional studies by their • age – 41 years nature can never prove cause and effect • CD4+ count – 627 cells/mm3 (that is, that integrase inhibitors cause • estimated duration of HIV infection – hypogonadism). Cross-sectional studies are six years a good starting point to begin to explore a research question. If something interesting Bear in mind that blood and other tests were done turns up, it can then be better understood in a largely at one point in time. We will return to this study of a more robust statistical design. aspect of the study later. 2. There were only 14 men who used integrase inhibitors in the French study. This is Results—Testosterone insufficient for drawing robust conclusions • Levels of antibodies that bind to testosterone about the impact of this class of medicines were elevated in 48% of participants. on testosterone levels (or anything else). The • Lower-than normal levels of testosterone were researchers stated that they were surprised found in 12% of men. by the association between integrase • Men who had low testosterone levels were inhibitors and low testosterone, which is more likely to have had HIV longer than men understandable because integrase inhibitors with normal testosterone levels. have been in use for about a decade in high- • Some men with low testosterone levels also income countries. Also, it is odd that no had thinner-than-normal bone density. other team of researchers has found this • Having a percentage of body fat greater than connection. Furthermore, in other studies, low 19% was associated with decreased testosterone testosterone has been found in HIV-positive levels (excess belly fat can convert some of the men who were not taking ART and, in men body’s testosterone into estrogen). who were taking ART before the introduction of integrase inhibitors.

Erectile dysfunction 3. The French researchers stated that they found an association between low testosterone Men with low testosterone were more likely to and integrase inhibitors. However, this have ED. However, even among men with normal conclusion could have been skewed by other levels of testosterone, 54% had ED. Men with ED factors that were unmeasured by their study. had been using ART longer (76 months) than men For instance, why were some patients given without ED (44 months). integrase inhibitor–based therapy and others were not? What was the medical history of these patients? Researchers did not apparently Specific anti-HIV drugs screen participants for the presence of all The researchers stated that they found a relationship major ED risk factors. Furthermore, the between the use of integrase inhibitors for more researchers did not address these points in than two years and the presence of hypogonadism. their analysis. It may be that doctors had Note that only 14 men were using integrase reasons for prescribing the anti-HIV drugs inhibitors in this study. We urge readers to treat that they did, and that by chance people with this finding with caution due to a number of low testosterone just happened to receive integrase inhibitor–based therapy. Such are Page 14 TreatmentUpdate 220 — Vol. 29 No. 2 ______TreatmentUpdate 220 — Vol. 29 No. 2 Page 15

some of the problems that can bedevil a cross- 2. Wunder DM, Bersinger NA, Fux CA, et al. Hypogonadism sectional study and the conclusions drawn in HIV-1-infected men is common and does not resolve during antiretroviral therapy. Antiviral Therapy. 2007;12(2):261-5. from such studies. 3. Collazos J, Esteban M. Has prolactin a role in the hypogonadal status of HIV-infected patients? Journal of the 4. What can be reasonably extracted from the International Association of Physicians in AIDS Care. 2009 Jan- present study is the following: Feb;8(1):43-6. 4. Lamers SL, Rose R, Maidji E, et al. HIV DNA Is frequently • free testosterone measurements are useful present within pathologic tissues evaluated at autopsy • some HIV-positive men have lower-than- from combined antiretroviral therapy-treated patients normal levels of testosterone with undetectable viral loads. Journal of Virology. 2016 Sep • ED is common among HIV-positive men 29;90(20):8968-83. 5. Jenabian MA, Costiniuk CT, Mehraj V, et al. Immune tolerance properties of the testicular tissue as a viral sanctuary What needs to be done site in ART-treated HIV-infected adults. AIDS. 2016 Nov 28;30(18):2777-2786. The role of HIV treatment on testosterone levels 6. Slama L, Jacobson LP, Li X, et al. Longitudinal changes (and ED) needs to be explored in a study of a over 10 years in free testosterone among HIV-infected and more robust statistical design. Such a study would HIV-uninfected men. Journal of Acquired Immune Deficiency have many more participants, but size alone is Syndromes. 2016 Jan 1;71(1):57-64. insufficient to prove cause and effect. Ideally, 7. De Ryck I, Van Laeken D, et al. Erectile dysfunction, as part of some randomized clinical trials, men testosterone deficiency, and risk of coronary heart disease in a cohort of men living with HIV in Belgium. Journal of Sexual would be screened for risk factors both for ED Medicine. 2013 Jul;10(7):1816-22. and low testosterone prior to initiation of ART and monitored while taking anti-HIV treatment. 8. Biebel MG, Burnett AL, Sadeghi-Nejad H. Male sexual function and smoking. Sexual Medicine Reviews. 2016 However, large, well-designed studies are expensive. Oct;4(4):366-375. In an era of austerity, it may take time to raise the funds necessary for such a large and well-designed study. The French researchers stated that they are engaged with a larger study to confirm their findings but did not state details as to that larger study’s design.

It is good that some researchers, such as the present French team, are interested in studying testosterone levels and why some HIV-positive men might have lower-than-normal levels. The findings from the French study are certainly interesting and should be seen as a beginning and not an end to understanding the issue of low testosterone and ED and their possible causes in HIV-positive men. Hopefully, the French study will stimulate other researchers to conduct further explorations on testosterone, ED and its relationship, if any, with HIV treatment. However, for now, any link between their findings on testosterone and the use of integrase inhibitors must be treated with caution until they are confirmed in a study that is statistically more robust.

REFERENCES: 1. Lachâtre M, Pasquet A, Ajana F, et al. HIV and hypogonadism: a new challenge for young-aged and middle- aged men on effective antiretroviral therapy. AIDS. 2017 Jan 28;31(3):451-453. Page 16 TreatmentUpdate 220 — Vol. 29 No. 2 ______

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