Medical Guidance

Recommendations Regarding PrEP Use – The “SwissPrEPared Guidance” Version 3.1.
(11. October 2024)

Benjamin Hampel1,2, Cate Esson3, Bernard Surial4, Lukas Baumann4, Raphael Bize5, Florian Vock6, Axel J. Schmidt7,8, Severin Läuchli9, Julia Notter10, Jürg Böni11, Philip Bruggmann12, Vanessa Christinet13, Marcel Stöckli14, Dominique L. Braun15, David Haerry16, Pilar Ustero Alonso17, Nicola Low18, Emmanuelle Boffi El Amari19, Enos Bernasconi20, Jan Fehr1

1Department of Public and Global Health, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland, 2Checkpoint Zurich, Zurich, Switzerland3CSS, Fondation PROFA, Lausanne, Switzerland, 4Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland, 5 Department of Epidemiology and Health Systems, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland, 6Swiss AIDS Federation, Zurich, Switzerland, 7 Department of Public Health, Environments and Society, London School of Hygiene and Tropical Medicine, London, United Kingdom, 8German AIDS Federation, Berlin, Germany,  9Dermatologisches Zentrum ZürichSwitzerland, 10Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland, 11Institute of Medical Virology, University of Zurich, Zurich, Switzerland 12Arud Centre for Addiction Medicine, Zurich, Switzerland  13Checkpoint Vaud, Lausanne, Switzerland, 14Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland,  15Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Zurich, Switzerland,  16Positive Council Switzerland, 17Laboratory of Virology and Division of Infectious Diseases, Geneva University Hospital, Geneva, Switzerland, 18 Institute of Social and Preventive Medicine, University of Bern, Switzerland,19Infectious Diseases and Internal Medicine Private Practice, Geneva, Switzerland, 20 Ente Ospedaliero Cantonale, Lugano, University of Geneva and University of Southern Switzerland, Lugano, Switzerland 

These recommendations were developed by the SwissPrEPared program to assist health care professionals in prescribing HIV Pre-Exposure Prophylaxis (PrEP). They will be adapted regularly, based on growing scientific knowledge and on quality assessment from the SwissPrEPared program. These recommendations can be used by every health care professional who prescribes PrEP or is asked about PrEP, but are not binding. The SwissPrEPared core team analyses on a regular basis how the recommendations are implemented in the clinical work. Deviations will be discussed within the SwissPrEPared network of physicians. The following recommendations are built on previously published recommendations by the Federal Commission for Sexual Health (FCSH) (1) and based on the results of the SwissPrEPared study and other international study results and recommendations i.e. the International Antiviral Society (IAS) (2), and the European AIDS Clinical Society (EACS)(3). Physicians can also join the national PrEP program SwissPrEPared to benefit from specific trainings and other support. If you are interested in joining the SwissPrEPared program, please contact www.swissprepared.ch. 

1. Efficacy of PrEP

Large trials have shown high efficacy of the combination of Tenofovir disoproxil (TDF) and Emtricitabine (FTC) used as PrEP among several risk groups. Efficacy has been shown to be highest among men who have sex with men (MSM). Both, daily and event-driven regimes showed an 86% efficacy to protect against HIV(4, 5). Efficacy among those who show good adherence is even higher and estimated around 99%(6). Although in a 2015 meta-analysis no difference in the efficacy of TDF/FTC was seen between sexes, many studies showed a reduced efficacy among cisgender women(7). For cisgender women adherence seems to be more important than among MSM, and a longer PrEP initiation time is needed to reach steady-state concentrations in the female genital tract tissue (8). New substances for the use of PrEP show promising results. Especially the long-acting injectable cabotegravir showed a better effectiveness than TDF/FTC among cisgender women but is so far not approved for prevention in Switzerland. Moreover, its high cost is an additional barrier for an off-label use. Only few data on PrEP exist for transgender men and women (9). Therefore, for both groups, the regime for cisgender women should be used. PrEP has also shown efficacy against HIV infection through needle-sharing among people who inject drugs, with a reduction of 49% in HIV incidence(10). However, for this study Tenofovir was used as a single drug and not in combination with Emtricitabine.

2. Situation in Switzerland

PrEP is recommended in Switzerland to be prescribed to persons at substantial risk of HIV since 2016(1). Since 2020, TDF/FTC has been approved by Swissmedic for the use of PrEP. As fo 1 July 2024, PrEP is covered by the compulsory health insurance as part of the SwissPrEPared program and in accordance with the FOPH reference document “Präexpositionsprophylaxe gegen HIV (HIV-PrEP)” from 31 October 2023 (40, 41). These recommendations should therefore not only assure the quality of care for people asking for PrEP, but also help to encourage physicians to offer medical supervision for people who are interested in taking PrEP.

3. Whom to prescribe PrEP

3.1. Health care providers’ role in the PrEP prescribing process

The final decision about taking PrEP is always made by the individual based on shared decision making with the prescribing physician. According to WHO, PrEP is recommended for populations whose annual HIV incidence is at least 3%(12). In Switzerland, this is mainly the case for some subgroups of MSM and transgender individuals who have sex with men(13). However, individual risk might be contextual: for instance, individuals not considered at risk in Switzerland may have a higher risk when travelling abroad; alternatively, behaviour may change over time and those not benefitting from PrEP at first may benefit later in the future. PrEP is often only needed for a certain period in life. This period can vary between a few days or years from person to person. Using PrEP as HIV prophylaxis is a personal and highly individual decision. Persons asking for PrEP are therefore in the best position to estimate their own risk. Together with health care professionals and provided information, they can establish the optimal prevention approach in a process of decision-making. Health care professionals should be capable to facilitate this decision-making process, provide easy-to-understand information, rule out contraindications for PrEP, and assess the existence of other medical conditions (such as anxiety disorders), since these could affect the decision-making process and adherence. Individuals who might benefit from PrEP, individuals who do not need PrEP and contraindications for PrEP are listed in Table 1.

3.2. Whom to recommend PrEP

Despite the importance of self-determination in the decision-making process for or against PrEP, certain persons deserve special attention as they are at a higher risk of acquiring HIV-infection and should therefore be informed and offered PrEP during medical consultations.

Individuals who benefit the most from PrEP are listed in Table 1:

Table 1: whom to recommend PrEP and contraindications for PrEP

PrEP: pre-exposure prophylaxis, GHB: gamma-Hydroxybutyric acid, GBL: gamma-Butyrolactone, STI: sexual transmitted infection, ART: antiretroviral therapy

3.3. People who inject drugs

Thanks to the good harm reduction programs, intravenous drug use is currently not a major risk for HIV in Switzerland(13). We therefore recommend maintaining these well-established and accepted harm reduction strategies and not to implement PrEP within these programs in general. PrEP may be considered in individual situations, especially for groups of people who inject drugs who so far cannot be reached with these programs, for example people who use intravenous drugs in a sexual setting or people who have not access to or fail to use sterile injecting material.

3.4. PrEP after HIV-post-exposure prophylaxis (PEP)

People, especially MSM, who have had an indication for PEP have been shown to have one of the highest risks for acquiring HIV(14). Information about PrEP should therefore be part of the consultations during the PEP treatment. If the person decides to start PrEP after PEP, the approach on how to start PrEP can be challenging and depends on the estimated risk for future HIV exposures. In some cases, waiting the recommended six weeks to perform a fourth generation HIV test after PEP was completed might be too long as further HIV exposure may have occurred in that time. In those cases, two practical approaches can be considered. Either an HIV PCR test can be performed before PrEP is started after a shorter window period, or PrEP can be started immediately after PEP. If PrEP is provided without a break after PEP, the point of seroconversion and therefore the time at which any HIV antibody and/or antigen test is reliable is unclear. There is not enough data to determine if PEP leads to a delay of the PCR result in case of HIV infection. Therefore, a PCR might help in the decision process but does not fully rule out HIV infection prior to PrEP initiation. In both situations – when the six weeks window period was not completed before PrEP was started – the limitations of the tests need to be discussed with the client and HIV screening tests need to be performed regularly during PrEP intake and when PrEP is discontinued. Table 2 can be used for considerations, even though each situation is individual. Consider contacting one of the SwissPrEPared physicians to discuss the case if needed.

Table 2: Considerations for future HIV risk in people who are prescribed PEP

There is not enough data on when a PCR is giving reliable results after PEP treatment.

4. Medication

So far, the combination of 245mg TDF and 200mg FTC is the only approved drug for PrEP in Switzerland.

Tenofovir alafenamide (TAF)

Tenofovir alafenamide 25mg (TAF) and FTC has been studied among MSM and transgender women and has shown noninferiority when used on a daily regime (15). In 2019 it was approved in the United States (US) for PrEP in MSM, but so far not in the European Union or Switzerland. This combination can be considered for off-label prescription for people with a high risk of HIV infection and a risk of developing kidney damage. However, the US approval for TAF/FTC is formally only for people with a GFR > 60mL/min (www.fda.gov). Another barrier is the high price of this product in Switzerland.

Lamivudine

WHO considers lamivudine and emtricitabine as interchangeable for HIV prevention (16). However, due to the lack of data for event-driven PrEP, we do not recommend this combination until further data is available. 

Tenofovir alone

TDF alone has not been studied in MSM and is therefore not recommended for HIV prevention in Switzerland.

Cabotegravir

Eight-weekly intramuscular injections of the integrase inhibitor Cabotegravir has shown to be superior to daily TDF/FTC in preventing HIV infections among MSM and transgender women(17) as well as among cisgender women(18). However so far real life data is missing. In the US, Cabotegravir has been approved for HIV prevention in December 2021. So far, it has not been approved for PrEP in Switzerland. Off-label use is possible in theory, but due to the high costs, less of an option in Switzerland.

Studies with other drugs are ongoing and may lead to more alternative PrEP regimens in the future.

5. Modes of PrEP use

Two regimens are well-studied and showed high efficacy in large clinical trials. The daily PrEP (one pill TDF/FTC every day)(4) and PrEP on-demand (also known as event-driven PrEP), according to the IPERGAY (Intervention Préventive de l’Exposition aux Risques avec et pour les Gays) protocol(5). Both regimens differ in the lead-in/lead-out phase and the duration of the PrEP intake. In clinical practice, we often see a combination of these two regimens, adapted to the individual situations.

It is therefore crucial that the PrEP user is certain about the correct lead-in/lead-out period of the individual intake regimen. Other regimens, such as continuous PrEP for four days a week (TTSS= Tuesday, Thursday, Saturday and Sunday) refer to retrospective data only and are therefore not recommended until further evidence is made available (studies still ongoing).

5.1. Regimen with a 7-days lead in/lead out period

The regimen that has been best studied on multiple populations is the daily use of PrEP with a dose of 245/200mg TDF/FTC every 24 hours. This regimen has shown high efficacy among MSM, transgender women, heterosexual cisgender men and women, and intravenous drug users. (4, 19-21). A one-week lead-in time is recommended to ensure adequate drug levels in genital and rectal tissues, and is recommended to be continued for one week after the last sexual exposure. (Figure 1)

Figure 1: dosage regimen for daily PrEP with a 7-days lead in/lead out time

figure 1

5.2. Options for shorter lead-in/lead-out phases for cisgender MSM: ’2-1-1’

For cisgender MSM, a shorter lead-in/lead-out phase is possible, according to the results of several studies that followed the IPERGAY protocol. (Also known as ‘on-demand’, ‘event-driven’ or ‘2-1-1’ regimen)(5, 22) Although PrEP in Switzerland is officially only licensed for daily use, the ‘2-1-1’ regimen is recommended by WHO and part of many international guidelines(2, 16). (Figure 2)

The IPERGAY study assessed PrEP with TDF/FTC given as two doses 2 to 24 hours before sex, one dose 24 hours after the first (double) dose, and one dose 24 hours later (‘2-1-1’ dosing). For consecutive sexual contacts, cisgender MSM were instructed to continue with one pill per day until two days after the last sexual encounter. With every new sexual encounter, PrEP was to be initiated with a double dose, unless the last PrEP dose had occurred within 7 days, in which case only one pre-exposure dose is recommended.

In clinical practice, we often see combinations of the daily and the ‘2-1-1’ regimen. For MSM the two regimens should be no longer seen as separate options but more as complementary. As sexual activity varies over time, the best mode of HIV protection may change as well. It is therefore crucial to check regularly if the PrEP user still knows the different options of how to start and how to stop.

  • ‘2-1-1’ is not recommended to risk groups other than cisgender MSM, especially not in women and transgender men since tenofovir levels were found 10 times lower in vaginal tissue than in rectal tissue and since clearance is faster.

  • No data on this regimen exists for intravenous drug users.

  • No data on this regimen exists for cisgender men who have sex with women (MSW). However, there is no clear rational why this regimen should not protect MSW for vaginal sex.

  • An intermittent dosing regimen is contraindicated for people with active HBV infection because of the risk of hepatitis flare and hepatic decompensation.

  • Adherence to PrEP seems to be more difficult with this regimen than with the daily one. It is therefore not recommended for people with known or likely adherence problems or with a more spontaneous sexuality(23).

Figure 2: regimen with shorter lead in/lead out option for cisgender MSM

figure 02

Some MSM might still prefer to start with a longer daily single-dose lead-in time, because they experience more side-effects with the double-dose, or they have more trust in the longer lead-in. However, in case of non-completion of the 7-days lead-in before a sexual contact, a double-dose of TDF/FTC needs to be taken at least 2h before the potential HIV exposure.

5.3. Duration for PrEP intake

As the frequency of sexual risks for HIV varies for each individual, different regimens for the duration of PrEP are used. Besides the daily use, which is the most common regimen, some people, especially people with less sexual partners, prefer an event-driven regimen, where the PrEP is only taken before and after a sexual contact. An intermediate form is the “Intermittent PrEP” or often called “holiday PrEP” where the PrEP is taken daily, but only over a limited period and with long intervals without PrEP. The event-driven regimen makes mostly sense for people who can use the ‘2-1-1’ lead-in/lead-out. The advantages, disadvantages and target population groups are listed in Table 3.  

Table 3: Advantages and disadvantages of different PrEP regimens and possible populations

6. Recommendations for clinical baseline and follow-up visits

Individuals asking for PrEP will first be assessed at baseline visit (see the description below). For those deciding to start PrEP, a second visit is recommended four weeks after PrEP initiation to evaluate early side effects and to rule out acute HIV infection missed at baseline visit (HIV test window period). After the second visit, a 3-monthly plan is recommended for all individuals using daily PrEP, 3–6-monthly for individuals using on-demand PrEP, and a 6–12-monthly plan for individuals at risk of HIV who decided not to start PrEP.

Each PrEP prescription should be for 90 pills, i.e. a maximum period of 3 months for individuals using PrEP daily, or maximum period of 6 months for individuals using non-daily PrEP to ensure appropriate monitoring.

6.1. General recommendations for every visit

Besides the recommended laboratory tests, each visit should:

  • evaluate the knowledge of the PrEP user about PrEP, HIV and STIs transmission
  • assess the risk for HIV according to the individual behavior.
  • evaluate adherence to medication and provide counselling on adherence
  • assess potential side effects related to TDF/FTC
  • assess co-medication for potential interaction
  • assess new medical conditions with potential effect on PrEP use
  • assess if the clients’ expectations regarding counselling are met
  • screen for depression and substance use
  • inform that PrEP does not protect 100% against HIV, and that regular HIV testing (every 3 months) is necessary to prevent resistance in the case of HIV infection despite PrEP.
  • assess clinical signs and symptoms of STIs
  • remind that condoms reduce acquisition of STIs and hepatitis C
  • For cis women: talk about birth control

6.1.1.Screening for mental health and substance use

To combine evaluation for mental health problems with PrEP consultations brings two advantages. On the one hand, people at higher risk for HIV and therefore benefit from PrEP, often belong to sexual and other minorities who are frequently exposed to stigmatization, discriminations and violence, putting them at higher risk for depression, drug addiction, and other mental health problems. Conversely, mental health problems, especially depression and addiction, have been shown to influence the adherence to PrEP intake. We therefore recommend evaluating mental health problems on every single PrEP visit, either in direct conversation or through a validated screening tool like the Patient Health Questionnaire-4 (PHQ-4), which is used in the SwissPrEPared consultation tool.

6.1.2. Counseling on adherence

Adherence to medication is the most critical part of PrEP effectiveness. We therefore recommend evaluation of PrEP adherence at every visit and to support PrEP users who struggle with adherence. Several measures have shown to improve adherence:

  • daily routine: Taking the PrEP medication always at the same time helps to include it in the daily routine. Combining PrEP intake with another daily routine might also help (putting the medication next to the coffee machine or next to the toothbrush)
  • setting a daily alarm, for example, on the smartphone or smartwatch
  • using a special smartphone application for adherence, for example “Prepared”
  • storing medication at several places, for example at home, at work, in the car
  • using a weekly medication dispenser
  • using a timer cap (especially for people who do not remember, if they already took their medication or not): A timer cap is a cap for the medication bottle, including a timer that shows when the bottle was opened the last time.

6.2. Baseline visit

The following should be addressed at the baseline visit:

  • Assessing the indication for PrEP, such as previous STIs, previous PEP prescription, sexual behaviour, drug use in combination with sex
  • Rule out contraindications (i.e., medical history, current medication (especially nephrotoxic drugs), osteoporosis, kidney and liver diseases, symptoms or signs consistent with an acute HIV-infection within the last six weeks).
  • Discussing advantages and disadvantages of the various PrEP regimens
  • Assessing serum creatinine level, alanin-aminotransferase (ALT)
  • Test for HIV- using 4th generation HIV test (rapid or laboratory test) to avoid resistance in case of undiagnosed HIV infection. People who experienced sexual HIV exposure in the six weeks prior to starting PrEP should either have an additional HIV-PCR test or should be tested again using a 4th generation HIV test four weeks after starting PrEP (i.e. at safety visit).
  • Hepatitis B status should be evaluated before starting PrEP but should not delay PrEP initiation. HBs antibody and HBs antigen negative individuals should be recommended the full course of three hepatitis B vaccine doses with titer control four to eight weeks after the third vaccine. People with an insufficient vaccination response (HBs-antibody less than 100 IE/l but more than 10 IE/l) should be recommended a single hepatitis B booster vaccination. Note: For individuals with active HBV infection (detectable HBsAg), discontinuation of TDF/FTC PrEP could lead to acute hepatitis flares or hepatic decompensation, particularly in patients with liver cirrhosis. Individuals with active hepatitis B infection should be referred to a medical doctor experienced in hepatitis B management. Careful monitoring of HBV infection and liver function is recommended after discontinuation of TDF/FTC. Any type of intermittent PrEP is not recommended for individuals with active hepatitis B infection.
  • Assessment hepatitis A vaccination status and offer of a full course of vaccine if not vaccinated.
  • Test for other STIs, even if the person decides not to take PrEP and regardless of whether they show symptoms of an STI or not. Syphilis should be screened using serological tests. The choice of syphilis test depends on previous history of syphilis and availability in the local laboratory. Syphilis rapid tests are not recommended due to insufficient sensitivity and specificity. Hepatitis C should be tested using serological tests or PCR, if acute HCV infection is suspected or after resolved/treated infection and for chlamydia and gonorrhea pooled PCR from rectal, pharyngeal and urethral/meatal/vaginal swabs should be performed. To reduce costs the 3 swabs can be pooled in a single tube for PCR.
  • Assess HPV vaccination status. If unvaccinated, offer the vaccine to every individual aged 26 years or younger (in Switzerland, vaccination is free as it is part of cantonal vaccination programs if the first dose is administered before the 27th birthday). Vaccinations against HPV for individuals over 27 are off-label and are not covered by the obligatory health insurance, however might be covered by some supplementary insurances.

In case of a contraindication for PrEP, the individual should be rescheduled within 7 days. If a person is already taking PrEP at baseline, the interventions will be adapted accordingly. If a person qualifies for PrEP but declines starting PrEP, a follow-up every 3 to 12 months is recommended to perform STI and HIV testing.

6.3. Safety-visit, 4 weeks after PrEP start

The following should be performed at a safety-visit:

  • assessment of side effects
  • re-assessment of PrEP indication and PrEP-regimen
  • assessment of PrEP adherence
  • HIV 4th generation test (automated laboratory test)
  • assessment of new medication (especially nephrotoxic drugs) and potential drug-drug interactions (https://www.hiv-druginteractions.org
  • measurements of serum creatinine level and ALT

6.4. Follow-up visits, 3 months after safety-visit and then every 3 months (can be extended to up to 6 months for non-daily PrEP use, depending on the individual risk)

  • All points as described under 6.3.
  • STI tests (syphilis, gonorrhea, chlamydia) are usually recommended every 3 months, but the frequency should be adapted if the PrEP user had no or very few sexual partners since the last visit (less than three). Of note, condoms show only partial protection against bacterial STIs. Tests for STIs are therefore also recommended if condoms are used.
  • Assessment of sexual risk behaviour (e.g.drug use in combination with sex)
  • Assessment of creatinine, glomerular filtration rate and proteinuria (urine dipstick) if further risk factors for kidney failure are known (diabetes, high blood pressure).

The following should be performed every 12 months:

  • ALT or more often if elevated (see A3.2),
  • protein/creatinine ratio (urine),
  • Hepatitis C screening or more often (3–6-monthly) if injection drug use (including intravenous and intracavernous injection) or receptive fisting is reported.

Table 4: Appointment schedule and key clinical assessments

PrEP= HIV Pre-Exposure Prophylaxis, STI= sexually transmitted infection, ALT= alanine transaminase

7. Management of side effects

7.1. PrEP start-up Syndrome

The PrEP start-up syndrome describes a variety of gastrointestinal and non-gastrointestinal symptoms that may occur in the first days and weeks of PrEP initiation. They are usually not associated with target organ damage, and self-limiting after a few days until a maximum 8 weeks(24).

Side effects can include nausea, flatulence, abdominal pain, dizziness, and headache. These symptoms usually occur early, but mostly disappear within the first month. They can often be managed with a symptomatic treatment like analgesia or anti-emetics, if necessary.

7.2. Alterations in kidney function due to TDF and recommended surveillance

TDF is known to induce proximal renal tubulopathy (PRT), known as Fanconi syndrome, in some individuals (25). This is a very rare side effect where the proximal renal tubules do not absorb certain electrolytes and amino acids, resulting in a loss in the urine. Proteinuria, hypophosphatemia, hypokalemia, hypouricemia, renal acidosis and glucosuria, with normal blood glucose level, are characteristic of PRT as well as possible renal insufficiency and polyuria. In PRT, it is possible that despite the presence of proteinuria and hypophosphatemia, the creatinine clearance remains within the normal range. Most often, only some of these abnormalities are observed, and it is not certain which tests discriminate best for TDF renal toxicity.

7.2.1. Frequency of kidney function testing

After starting to take TDF for PrEP, a small but statistically significant decrease in creatinine clearance may be seen from baseline, which resolves after stopping TDF/FTC(26). There are no data for people with eGFR<60 mL/min, so continuing TDF/FTC if eGFR falls to below 60 mL/min/1.73 m2 is not advised.

Reduction in creatinine clearance while taking TDF/FTC alone is a rare side effect and many international guidelines now recommend checking the kidney function in healthy PrEP clients with no other risks for kidney failure only once or twice a year (27, 28). Although 6–12-monthly tests might be sufficient for people without risk factors, we recommend routine checking of kidney function at every visit for people considered at greater risk, for example, people with:

  • age above 40 years
  • GFR <90mL/min/1.73m2 at baseline
  • risk factors for renal disease
    • history of diabetes, hypertension or previous renal disease
    • nephrotoxic co-medication
    • family history of renal disease
    • substance use/misuse (cocaine)

7.2.2. How to screen for kidney function

  • Check serum creatinine with GFR calculation at baseline for all PrEP initiators. Consider lengthening the time interval between kidney checks if initial checks are stable (3-6 months) in the absence of concomitant risk factors
  • Check serum creatinine with GFR calculation at baseline and at each 3-monthly checkup for those with risk factors or considered at risk
  • Check protein/creatinine ratio annually (serum creatinine, urine protein and creatinine) for all PrEP users. These checks are not needed for individuals with rare on-demand PrEP use and no risk factors for renal disease.
  • In people with a high muscular mass, e.g., bodybuilders, GFR may be calculated as incorrectly low if using the CKD-EPI formula and can be recalculated using Cockcroft-Gault formula which includes body weight.
  • Cystatin C can more accurately estimate the renal function in cases of high muscular mass and high doses of creatine supplements

7.2.3. Stepwise approach in case of reduced GFR

In case of an alteration in kidney function, we recommend a stepwise approach (fig.3)

  • Recheck creatinine and eGFR to confirm abnormality.
  • If weight is out of the normal range or there is high muscular mass, verify a decrease by using a weight adapted formula, for GFR (e.g., Cockcroft-Gault) and consider checking cystatin C levels.
  • Take a full medical history including investigating substance abuse/use
  • Check all medication (including over-the-counter drugs, in particular NSAID)
  • Ask about anabolic steroid use.
  • Check for use of nutritional supplements, including protein or creatine
  • Ask about family history for kidney disease, hypertension or diabetes

If a decrease in the GFR is confirmed, we recommend the following further investigations:

  • Measure blood pressure
  • Laboratory tests:
    • Serum phosphate and creatinine
    • Serum glucose
    • urinalysis for signs of hematuria, glucosuria and proteinuria
    • urine spot for protein, phosphates and creatinine with a calculation for protein/creatinine ratio and percentage of phosphate reabsorption.
    • Fractional excretion of uric acid tested in urine spot (fasting if possible)

If laboratory tests confirm PRT, stop TDF/FTC and test kidney function again after 4 weeks. A change from a TDF to a TAF-based PrEP regimen can be considered(29). However, TAF has no label for prevention in Switzerland, and there are no generic versions available in Swiss pharmacies. Formally, the FDA label is only for people with a GFR >60 mL/min.

If lab results do not confirm PRT, still consider stopping PrEP, especially if GFR is <60 and refer the client to a kidney specialist.

Figure 3: Stepwise approach in case of alteration in kidney function

GFR= Glomerular filtration rate, NSAID= nonsteroidal anti-inflammatory drug, PRT= proximal renal tubulopathy, TDF= Tenofovir disoproxil fumarate, FTC= Emtricitabine

7.3. Increase in levels of liver enzymes

TDF can cause a mild to moderate increases in liver alanine aminotransferase (ALT) in some people living with HIV (30) and in some PrEP users (31). The clinical relevance of these findings is unclear, and most guidelines do not recommend including ALT tests in regular PrEP visits (27, 28). To our current knowledge, cases of severe PrEP induced liver injury have not been reported. As mild elevation of liver enzymes is common in the general population (prevalence estimates mostly >10%) (32), elevation of liver enzymes in PrEP clients is likely to have other origins than TDF induced liver toxicity, e.g. alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH). Liver toxicity due to recreational drug use and viral hepatitis might be more common in PrEP clients than in the general population.

The benefits (early detection of disease and potential drug toxicity) and risks (overdiagnosis, stopping PrEP unnecessarily, complications of further examinations, costs) of screening in PrEP clients are unclear, and evidence informing a recommendation is lacking. Furthermore, the upper limit of normal (ULN) for transaminases is disputed. Values in the normal range do not exclude liver diseases (33), and subsequent diagnostic evaluation of mildly elevated transaminases often do not find specific liver diseases (34). By taking into consideration that PrEP is prescribed to healthy clients as prevention, we recommend testing for ALT before starting PrEP, and every 12 months thereafter, until more data on liver toxicity is available.

If elevated liver enzymes are observed, other reasons than PrEP intake should be considered. For non-acute and asymptomatic patients, we propose a stepwise approach detailed in the algorithm below (fig.4), which we developed in adaptation to the EACS guidelines (3). When a persistent or significant ALT-elevation (>2x ULN) is observed, a basic assessment of the most common liver pathologies should be conducted. In the basic assessment, toxicity due to other medication and substances (e.g., anabolic steroids, cocaine, ecstasy), ALD, NASH, hemochromatosis, viral hepatitis and symptoms indicative of systemic diseases involving the liver should be evaluated. Individuals should be evaluated for liver steatosis with ultrasound and, if present, a fibrosis risk assessment using an established score conducted (e.g., Fib-4) (33). A low risk score allows for periodical reassessment. For moderate results preforming transient elastography and for high-risk scores, a hepatologist referral is recommended (3, 33). If available, a transient elastography might be considered in the basic evaluation, but in most guidelines, ultrasound is recommended as the primary first screening tool for NAFLD(3, 33, 35).

If no cause can be identified, and the elevation of liver enzymes persists, rare causes (autoimmune liver and metabolic liver diseases) should be evaluated. Furthermore, stopping PrEP and a hepatologist referral should be considered. For significantly elevated liver enzymes (≥ 5.0 x ULN), acute onset and/or symptomatic patients, the proposed algorithm should be used with caution and a timely, comprehensive evaluation and hepatologic referral should be evaluated. It is important to emphasize that the finding of liver steatosis might have multiple origins. If, despite lifestyle interventions, the ALT-elevation progresses or fibrosis develops, other causes should be considered.

Figure 4: Stepwise approach for elevated ALT

2 Alcohol and drug use leading to elevated liver enzymes is often caused by a problematic use or addiction which cannot be easily stopped. Counsel to stop and retest after 1 month is often insufficient in such situations. Consider referral to addiction medicine
 

ULN=Upper Limit of Normal, PrEP=Pre-Exposure Prophylaxis, BMI=Body-Mass-Index, ALAT=Alanin-Aminotransferase, ASAT=Aspartate-Aminotransferase, GGT=Gamma-Glutamyl Transferase AP=Alkaline Phosphatase, INR= International Normalized Ratio, CBC=Complete Blood Count, HbA1c= Glycated Hemoglobin, TSH=Thyroid Stimulating Hormone, TF=Transferrin, HCV= Hepatitis C Virus, HbsAG= Hepatitis B Antigen S HAV= Hepatitis A Virus, HEV= Hepatitis E Virus IgA Immunoglobulin A, IgM= Immunoglobulin M, IgG= Immunoglobulin G, LKM= Anti–Liver-Kidney Microsomal Antibody, CK= Creatine Kinase

7.4. Decrease in bone mineral density (BMD)

The use of TDF in people living with HIV is associated with an early decrease of 3-4% of bone mineral density after treatment start, especially when co-administered with a boosted protease inhibitor (36). In HIV-uninfected individuals, using TDF/FTC as PrEP, this effect seems to be less pronounced (~1%) without increased fracture risk (26, 37-39). No routine screening with bone densitometry is necessary for individuals using PrEP. Increased physical activity, smoking cessation, and reduction in alcohol consumption may reduce the long-term fracture risk in all individuals, and calcium and vitamin D supplementation may be considered if intake is insufficient. The ten-year fracture risk should be assessed in individuals with risk factors for osteoporosis (e.g., history of falls or fracture, use of glucocorticoids) using the FRAX score, and bone densitometry should be performed in those with a high fracture risk to further assess the need for treatment. As the clinical consequences of the bone density reductions associated with PrEP remain unclear, the decision if TDF/FTC based PrEP should be prescribed in the presence of osteoporosis depends on the individual’s risk for HIV infection.

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