17.9 — HIV

In 1996, a person diagnosed with HIV in a wealthy country had a median survival of around ten years, and the treatment was a handful of toxic drugs taken many times a day.

Today, a person diagnosed promptly and treated has a life expectancy close to the general population, on one tablet a day.

And they cannot transmit the virus sexually.

That second sentence is the most consequential fact in this chapter, and a substantial proportion of the public — and a proportion of clinicians — still do not know it.

What HIV does

A retrovirus (Chapter 17.2) that infects CD4 helper T cells — the coordinating cells of the adaptive immune system (Chapter 13.2).

Which is why it is so destructive. The helper T cell activates B cells, activates killer T cells, and activates macrophages. Remove it and the entire adaptive response degrades, even though the other cells are themselves uninfected.

The life cycle, and each step is a drug target:

Binding to CD4 and a co-receptor — usually CCR5, which is the gene He Jiankui edited (Chapter 2.9), and people with a naturally occurring deletion in both copies of CCR5 are largely resistant to HIV infection.

Reverse transcription — RNA to DNA.

Integration — the DNA copy inserted into the host genome.

And integration is why HIV cannot currently be cured. The provirus sits inside long-lived resting cells, producing nothing, invisible to both the immune system and to drugs — and it reactivates whenever treatment stops.

This latent reservoir is the entire obstacle to cure, and it is established within days of infection.

Transcription, assembly and budding.

And its mutation rate is extremely high — no proofreading, and around 10¹⁰ new particles a day in untreated infection. Which is precisely why single-drug treatment fails within weeks and why combination therapy works.

The course, untreated

Acute infection — 2 to 4 weeks after exposure, in around 50 to 90 percent of people.

Fever, rash, sore throat, swollen nodes, muscle aches — a glandular-fever-like illness.

And this is the window of highest infectiousness, because the viral load is enormous — and the point at which it is most often missed, because it looks like any viral illness.

Which is why a low threshold for testing anyone with an unexplained febrile illness and a possible exposure matters, and why standard antibody tests may still be negative at this stage.

Clinical latency — years to decades. Not dormancy: the virus replicates continuously and CD4 cells are destroyed and replaced, with the count falling by around 50 to 100 per year.

AIDS — defined by a CD4 count below 200, or by the presence of an AIDS-defining illness.

And the opportunistic infections appear in a predictable order as the count falls, which is genuinely useful:

Below 200 — Pneumocystis pneumonia, oesophageal candidiasis. Below 100 — toxoplasmosis of the brain, cryptococcal meningitis. Below 50 — CMV retinitis, disseminated mycobacterial infection.

Tuberculosis occurs at any CD4 count and is the leading cause of death in people with HIV worldwide (Chapter 17.8).

Certain cancers also increase — Kaposi sarcoma, lymphoma, cervical cancer — and all are virus-driven, which is direct evidence of what immune surveillance normally does (Chapter 13.8).

Testing

Fourth-generation tests detect both antibody and p24 antigen, which shortens the window period to around 18 to 45 days.

Self-testing kits are available and have increased testing substantially.

And the case for testing widely is straightforward: a substantial proportion of transmission comes from people who do not know they are infected, and late diagnosis — with a CD4 count already below 350 — remains common and is the main determinant of poor outcome.

Which is why opt-out testing in emergency departments and general practice in higher-prevalence areas is now recommended — offering the test as routine rather than requiring a reason.

Treatment

Antiretroviral therapy: combination treatment, started immediately on diagnosis regardless of CD4 count.

"Treat all" replaced the old approach of waiting for the count to fall, after trials showed clear benefit to starting early — both for the individual and for preventing transmission.

Modern regimens are typically a single tablet once daily, combining three drugs. Integrase inhibitors are now the backbone of first-line treatment, being effective, well tolerated and slow to develop resistance.

And long-acting injectable regimens given every one to two months are now available, which changes daily life substantially for people who struggle with tablets.

The goal is an undetectable viral load, achieved in the great majority within 3 to 6 months.

And treatment is lifelong, because of the latent reservoir.

U=U

Undetectable equals untransmittable.

A person on effective treatment with a sustained undetectable viral load cannot transmit HIV sexually.

This is not a probabilistic statement. The PARTNER studies followed thousands of couples over many years of condomless sex with an undetectable positive partner, and recorded zero linked transmissions.

It is endorsed by every major health body.

And its implications are enormous, medically and socially. It means treatment is prevention. It means serodifferent couples can conceive naturally. It means the basis for criminalisation, exclusion and much of the stigma is gone.

It is one of the most important public health messages of the last twenty years, and it is under-communicated.

Prevention

PrEP — pre-exposure prophylaxis. Antiretroviral medication taken by an HIV-negative person at risk, reducing sexual transmission by around 99 percent when taken as prescribed.

Available as a daily tablet, as event-based dosing for some groups, and as a two-monthly injection.

PEP — post-exposure prophylaxis. Started within 72 hours, ideally within hours, and taken for 28 days.

Preventing mother-to-child transmission — and this is the clearest success.

Untreated, transmission occurs in around 15 to 45 percent of pregnancies. With antiretroviral treatment, elective delivery where indicated, infant prophylaxis and appropriate infant feeding, transmission falls below 1 percent.

Several countries have been certified as having eliminated mother-to-child transmission, and it is one of the most effective interventions in all of medicine.

Voluntary medical male circumcision reduces female-to-male transmission by around 60 percent, and is part of prevention programmes in high-prevalence settings.

Condoms, harm reduction and needle exchange for people who inject drugs.

And a vaccine remains elusive. Decades of effort, several large trials, no effective product — because the virus mutates rapidly, integrates early, and the correlates of protective immunity are not established. Broadly neutralising antibodies are the current focus.

Cure

Two people have been cured, and the circumstances explain why it is not generalisable.

Timothy Ray Brown, the "Berlin patient", and Adam Castillejo, the "London patient", both received bone marrow transplants for leukaemia from donors with the double CCR5 deletion.

The transplant replaced their immune system with cells the virus cannot enter.

A handful of further cases have followed.

And bone marrow transplantation carries a mortality of several percent — vastly higher than the risk of living with treated HIV. It is a cure that is only justifiable when the transplant is needed anyway for cancer.

Research directions: "shock and kill" — activating the latent reservoir so it can be cleared; gene editing of CCR5; and therapeutic vaccines. None has yet produced sustained remission off treatment in more than isolated cases.

Where it stands

Around 39 million people live with HIV. Around 1.3 million new infections a year, down from a peak of around 3.2 million in the mid-1990s. Deaths down from around 2 million a year to around 630,000.

Around 30 million are on treatment — from essentially none in 2000.

That expansion, driven by generic manufacturing, international funding and price reductions, is one of the largest public health achievements of the century.

What remains: key populations are underserved and criminalised in many countries; stigma keeps people from testing; and around a quarter of people with HIV do not know it.

And the practical summary for a reader is short. Test — it is quick, free in most systems, and available as a home kit. If you are at ongoing risk, PrEP works. If you have had a possible exposure, PEP within 72 hours works. And if you are positive, treatment works, you will live a normal lifespan, and you will not pass it on.

None of those sentences could have been written in 1995.

What the next page fixes

Chapter 17.10 covers the hepatitis viruses — five different diseases sharing a name, one of which has gone from incurable to curable within a decade.