The short answer: Firm lumps under the skin, called injection-site nodules, are the most common side effect of Yeztugo (lenacapavir), the twice-yearly HIV PrEP shot. In the two main clinical trials, 63% to 64% of people who got Yeztugo reported a nodule, and nodules from the first injections took a median of about 10 to 11.5 months (297 and 350 days) to go away. Most injection-site reactions were mild or moderate, none were rated serious, and they were reported less often with later injections.

If you've just had your first Yeztugo injections and can feel a bump on your belly, you're far from alone. Below, we walk through what the FDA-approved prescribing information and the CDC say about these lumps: why they form, how big they get, how long they tend to last, what may ease discomfort, the other common side effects, why you need an HIV test before every injection, and when to call your clinician.

What is Yeztugo, and how is it given?

Yeztugo is a prescription medicine approved for HIV pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents who weigh at least 35 kg (77 lb) and are at risk for HIV. According to the Yeztugo prescribing information on DailyMed, the schedule set out in the label works like this:

• Starting (Day 1): two injections under the skin, given by a health care provider, plus two tablets by mouth.
• Day 2: two more tablets.
• After that: two injections every 6 months (26 weeks) from the date of the last injection, within a window of plus or minus 2 weeks.

The injections go into the stomach area (abdomen), with the thigh as an alternative site. They are not given in the arm. In the PURPOSE 1 trial, no HIV infections occurred among the 2,134 participants randomized to Yeztugo, compared with 16 among 1,068 on daily Truvada. In PURPOSE 2, there were 2 infections among 2,179 on Yeztugo versus 9 among 1,086 on Truvada. The label also notes that Yeztugo "is not always effective" in preventing HIV. For the bigger picture on access, see our news post on the global push to reach 3 million people with the twice-yearly PrEP shot.

Why do Yeztugo shots cause lumps?

Yeztugo is designed to last for months. After the injection, the medicine forms a small reservoir under the skin, which the label calls a "drug depot," and slowly releases from there. The prescribing information tells clinicians to advise people that this depot "may lead to a nodule at the injection site" in some individuals.

The label also reports that in a separate study of people living with HIV who received lenacapavir injections (CAPELLA), skin biopsies of some nodules or hardened areas showed a foreign-body or granulomatous response, which is a type of local inflammation around the injected material.

How common are injection-site nodules?

Very common. The label's safety data come from PURPOSE 1 (cisgender adolescent girls and young women in South Africa and Uganda) and PURPOSE 2 (cisgender men, transgender women, transgender men and gender-nonbinary people in seven countries, including the United States). In both trials, the comparison groups took daily oral PrEP plus placebo injections, so researchers could compare reactions to the injection itself.

• Any injection-site reaction: 69% with Yeztugo vs 35% with placebo injections in PURPOSE 1; 83% vs 69% in PURPOSE 2.
• Nodules specifically: 64% with Yeztugo vs 17% with placebo injections in PURPOSE 1; 63% vs 39% in PURPOSE 2.
• Severity: most reactions were mild (Grade 1) or moderate (Grade 2). Severe (Grade 3) reactions were reported in 0.2% of Yeztugo participants in PURPOSE 1 and 0.6% in PURPOSE 2. None were classified as serious.
• Stopping because of injection-site reactions: 0.2% of Yeztugo participants in PURPOSE 1 and 1.2% in PURPOSE 2.

In both trials, the label says, injection-site reactions were reported less often with later injections.

How long do Yeztugo lumps last, and how big do they get?

Nodules clear up more slowly than other injection-site reactions. For nodules linked to the first injections, the label reports:

• PURPOSE 1: a median duration of 350 days; the middle half of durations ranged from 182 to 470 days.
• PURPOSE 2: a median duration of 297 days; the middle half ranged from 176 to 423 days.
• Size: the median of each person's largest measured nodule was 3.0 cm (about 1.2 inches) across in both trials.

In plain terms, many people can expect a lump from their starting injections to last most of a year, and for some it lasts longer. The CDC's clinical recommendation for injectable lenacapavir PrEP puts it this way: nodules "can last for several months to more than a year." The FDA-approved patient information adds that a lump or hardened skin "may be felt but not seen."

What other injection-site reactions can happen?

Besides nodules, the label lists these reactions at the injection site in at least 2% of people who got Yeztugo:

• Pain: 31% in PURPOSE 1 and 56% in PURPOSE 2 (compared with 24% and 53% for placebo injections).
• Induration (hardened skin): 4% and 16%. Like nodules, it lasted longer, with a median of 173 and 151 days.
• Redness: 17% in PURPOSE 2 (19% with placebo injections).
• Swelling, itching, bruising and warmth were less common.

Not counting nodules and induration, the other injection-site reactions were short-lived: a median of 9 days in PURPOSE 1 and 4 days in PURPOSE 2.

What helps with Yeztugo lumps and soreness?

The prescribing information doesn't list home-care steps for nodules. The CDC recommendation says that ice packs and topical or oral pain relievers used before and after the injection "might alleviate some signs and symptoms" of injection-site reactions. Check with your clinician before using any medicine, including over-the-counter pain relievers, since Yeztugo can interact with other drugs.

Injection technique matters, too. The label warns that injecting into the skin layer instead of under it (intradermal injection) has been linked to serious injection-site reactions, including skin breakdown (necrosis) and open sores (ulcers). The CDC notes that inserting the needle at too shallow an angle is thought to contribute to injection-site reactions, and that the manufacturer recommends a 90-degree angle.

Questions you might ask your clinician:

• Where on my abdomen (or thigh) will the injections go, and can we plan sites for future visits?
• Is it OK for me to use ice or a pain reliever before or after my appointment?
• What should a normal nodule look and feel like, and what changes should I report?
• Do any of my other medicines, supplements or herbal products interact with Yeztugo?

What are the other common side effects of Yeztugo?

According to the label, the most common side effects (reported by at least 5% of participants) were injection-site reactions, headache and nausea. Rates for side effects attributed to the study drug were:

• Headache: 7% in PURPOSE 1 and 2% in PURPOSE 2 (8% and 2% with Truvada).
• Nausea: 5% and 2% (11% and 4% with Truvada).
• Dizziness, vomiting and diarrhea: 4% each in PURPOSE 1, and 2% or less in PURPOSE 2.

Few people stopped because of side effects of any kind: under 1% in PURPOSE 1 and 1% in PURPOSE 2. These figures come from clinical trials, and the label cautions that trial rates may not reflect what happens in everyday practice.

Why do you need an HIV test before every Yeztugo injection?

This is the most important safety point on the label, and it's in a boxed warning. Yeztugo alone is not a complete HIV treatment. If someone has HIV that hasn't been diagnosed and receives only Yeztugo, the virus can become resistant to the drug, and drug-resistant HIV has been seen in this situation. That's why the label says:

• People must test negative for HIV before starting Yeztugo and before every injection, using an FDA-approved or cleared test that can detect acute or early HIV infection.
• Yeztugo is not for anyone whose HIV status is positive or unknown.
• Anyone who acquires HIV while on Yeztugo must switch to a complete HIV treatment regimen.

The patient information also asks people to tell their provider about any flu-like illness in the month before starting, or at any time while on Yeztugo, because early HIV can cause symptoms like fever, tiredness, sore throat, rash or swollen glands. Yeztugo can stay in the body for 12 months or longer after the last injection, so the label says other forms of PrEP should be considered, and started within 28 weeks of the last injection, if someone stops Yeztugo but still wants protection. If regular testing is new to you, our guide to how often to get tested for STDs can help.

When should you call a clinician?

The patient information says to tell your health care provider about any injection-site reactions or other side effects. Reach out promptly if:

• The skin at the injection site shows signs of severe damage or forms an open sore.
• A lump or sore spot is getting worse instead of better, or anything about it worries you.
• You develop flu-like symptoms, or you think you were exposed to HIV.
• Your next injection may be delayed by more than 2 weeks. The label says to call right away to discuss PrEP options.
• You become pregnant or plan to, or you're starting a new medicine.

For emergencies, call 911. You can also report side effects to the FDA through MedWatch or by calling 1-800-FDA-1088.

What do Yeztugo side effects mean for dating?

A small, firm bump on your belly is a common, expected part of using this medicine, and it's often something a partner won't see. If a partner does notice it, a simple explanation usually does the trick: it's where your PrEP shot slowly releases medicine. A few other things to keep in mind:

• PrEP doesn't prevent other STIs. The label recommends using Yeztugo as part of a broader prevention plan, including condoms. Our guide to layering condoms, antivirals and PrEP explains how the pieces fit together.
• Treatment is prevention, too. If your partner is living with HIV, effective treatment matters as much as PrEP. Learn what U=U (undetectable = untransmittable) means, see our post on serodiscordant couples, and read about long-acting HIV treatment in our Cabenuva real-world study post.
• Talk openly and date safely. Share what you're comfortable sharing about PrEP and testing, never pressure a partner, and make sure everything is consensual. Meet new matches in public and verify who you're talking to. Disclosure expectations and legal duties differ by state.

FAQ

Are Yeztugo lumps permanent?

Not usually. In the trials, nodules from the first injections lasted a median of 297 to 350 days. For some people they lasted longer: in PURPOSE 1, about a quarter of nodules lasted 470 days or more. The CDC describes them as lasting "several months to more than a year."

Do the lumps get better with later injections?

The label says injection-site reactions were reported less often with subsequent injections in both PURPOSE trials.

Does a lump mean the shot isn't working?

The label explains nodules as a result of the drug depot that forms under the skin, and it doesn't describe them as a sign the medicine has failed. Protection depends on staying on schedule and testing negative before each injection. Ask your clinician if you have concerns.

Can Yeztugo be injected in the arm?

No. The label says Yeztugo is injected under the skin of the abdomen, with the thigh as an alternative site.

Is Yeztugo the same as Cabenuva or Apretude?

No. Yeztugo contains lenacapavir and is given every 6 months for PrEP. Cabenuva is a long-acting HIV treatment for people living with HIV, and Apretude is a different long-acting PrEP injection that contains cabotegravir.

The bottom line

Lumps at the injection site are the most common side effect of Yeztugo. They show up in roughly two out of three people in the trials, often last most of a year, and are usually mild. Other side effects, like headache and nausea, were much less common. The most important rule isn't about the lumps at all: you need a negative HIV test before every injection. Bring any questions or concerns to your clinician. And if you're looking for people who understand HIV prevention and life with HIV, explore HIV dating on MeetPositives.

Sources

• Gilead Sciences, Inc. YEZTUGO (lenacapavir) tablets and injection, US prescribing information and FDA-approved patient information (revised August 2026), via DailyMed, National Library of Medicine.
• Centers for Disease Control and Prevention. "Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025." MMWR, Vol. 74, No. 35.
• US Food and Drug Administration, MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

This article is for general information only and is not medical or legal advice. It does not create a doctor-patient relationship. Talk with a licensed health care provider about your own situation. Laws vary by state; for legal questions, talk with a licensed attorney.