HIV Treatment: ART Regimens, Failure and TB Co-Infection

HIV treatment with antiretroviral therapy (ART) should start in everyone diagnosed with HIV, whatever the CD4 count. The standard first-line regimen combines two nucleoside reverse transcriptase inhibitors with an integrase inhibitor, usually in one daily pill. The regimen must be fitted to the whole patient, and when therapy fails, often because of missed doses and sometimes signalled by tuberculosis, the doctor must tell an adherence problem from drug resistance.

That sequence formed the treatment half of the masterclass given by Dr. Neha Rastogi, Senior Consultant Infectious Diseases, Fortis Memorial Research Institute, Gurgaon, India. She runs an HIV clinic that has cared for about 2,300 patients over four and a half years, drawn from districts across her state, and she presented the subject through cases from that clinic. Her central principle was blunt: "You have to treat a person. You are not treating a virus." This article follows her reasoning from the decision to treat through regimen design, treatment failure, tuberculosis co-infection and the prospects for a cure. Diagnosis and staging are covered in the complete guide to tuberculosis and HIV.

When to start HIV treatment: at diagnosis, whatever the CD4 count

Every person diagnosed with HIV should start antiretroviral therapy, regardless of CD4 count, the level of the white blood cells that HIV destroys. Dr. Rastogi Panda illustrated why with a couple. The husband was diagnosed in 2013 with a CD4 count of 330, and his wife also tested positive, because of their ongoing exposure before he was diagnosed. He was started on the regimen of that era, based on zidovudine, lamivudine and nevirapine, and remained well on it with a controlled viral load. His wife, whose CD4 count was then 960, was kept under routine follow-up, because guidelines at the time made the decision to treat depend on the CD4 count.

Almost twelve years later she presented with a CD4 count that had fallen to 670, asking whether she should now start treatment. The answer is an unequivocal yes. Since 2015, the World Health Organization (WHO) has recommended treating everyone with HIV irrespective of CD4 count, and India adopted the same "treat all" strategy two years later. A falling count is not the trigger; the diagnosis itself is.

The two goals of HIV treatment

Antiretroviral therapy has two objectives, and Dr. Rastogi Panda states them to every patient. The viral load should be as low as possible, ideally undetectable. The CD4 count, the measure of the patient's immunity, should rise progressively. Every other decision about the regimen serves those two goals.

How antiretroviral drugs work: the HIV life cycle

Each class of antiretroviral drug blocks a different step in the virus's life cycle, which is why combinations work. The cycle runs as follows:

1. Entry. The virus binds to receptors on the CD4 cell and enters it. Entry inhibitors block this first step.
2. Reverse transcription. Inside the cell, the viral enzyme reverse transcriptase copies the virus's RNA into DNA. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) act here, as do the non-nucleoside reverse transcriptase inhibitors such as efavirenz and nevirapine.
3. Integration. The viral DNA enters the nucleus and is spliced into the host cell's own DNA by the enzyme integrase. Integrase inhibitors, such as dolutegravir, raltegravir and bictegravir, block this step. Because integration is so crucial to the virus, Dr. Rastogi Panda noted, this class contributes heavily to the overall efficacy of modern therapy.
4. Assembly and release. The host cell is used to manufacture new viral RNA and proteins, which assemble into new virus particles that leave the cell to infect others. Protease inhibitors act at this final stage, preventing the new particles from maturing into infectious virus.

Lenacapavir, a recent drug, works differently: it is a capsid inhibitor that disrupts the protein shell of the virus and acts at both early and late stages of the cycle. Its role in prevention is covered in the article on PrEP and PEP.

First-line ART regimen: two NRTIs plus an integrase inhibitor

Triple-drug therapy is, in Dr. Rastogi Panda's phrase, the heart and soul of HIV treatment. The older regimens built on zidovudine and nevirapine gave way to tenofovir- and efavirenz-based regimens, and those in turn to integrase-based therapy. Today the preferred combination is two NRTIs plus one integrase inhibitor.

The drugs most commonly available in Asian and African settings are:

• NRTI backbone: tenofovir (as tenofovir disoproxil fumarate, TDF, or tenofovir alafenamide, TAF), lamivudine and emtricitabine
• Integrase inhibitor: dolutegravir or bictegravir

Combinations of the two arms are now available as a single pill taken once a day, at any time of day, with little interaction with food. Alongside the pill, the modern approach to HIV care centres on prevention. HIV's main harm is to weaken immunity and raise the risk of infection. Care therefore combines viral suppression with tuberculosis preventive therapy and vaccination, as in any other immunocompromised patient.

Building the regimen around the patient

The difficulty in starting ART is rarely the regimen itself. It lies in everything else the patient brings. Dr. Rastogi Panda's illustration was a woman in her early fifties seen in her clinic a few months earlier. She was asymptomatic; her husband had been HIV positive. She was postmenopausal with osteopenia, had used budesonide inhalers for asthma for some 14 or 15 years, had high blood pressure and was obese. Her haemoglobin was 9.9, her CD4 count 398 and her viral load relatively high; screening for syphilis, hepatitis B and hepatitis C was negative.

TDF would ordinarily be a natural choice, but it carries two major side effects: loss of bone density and kidney damage. In a woman already close to osteoporosis, with hypertension and obesity placing her kidneys at risk, that regimen is very difficult to justify. As patients with HIV live longer, the regimen has to account for:

• Comorbidities: diabetes, hypertension and kidney disease
• Psychiatric illness, because many psychiatric medicines interact with antiretroviral drugs
• Neurological conditions such as parkinsonism and dementia
• Pill burden. Even moving from one pill to two creates a real problem for a patient who already takes a long list of medicines.
• Dosing frequency and food requirements: once daily versus twice daily, with or without food
• The genetic barrier to resistance of the chosen drugs, meaning how many mutations the virus needs before a drug stops working

Simpler regimens: two-drug therapy and long-acting injectable ART

The direction of HIV therapy is towards simplicity. Dr. Rastogi Panda described two developments.

Two-drug therapy. Where triple therapy was once the only option, two-drug regimens are now used. Fewer drugs mean simpler treatment, lower cost, fewer adverse effects and fewer drug interactions. She has already initiated two-drug therapy in about 670 of her patients.

Long-acting injectable therapy. Beyond the daily pill, long-acting regimens replace oral therapy with injections given every one or two months. In answer to a question, Dr. Rastogi Panda described cabotegravir, a long-acting integrase inhibitor, combined with rilpivirine, a non-nucleoside reverse transcriptase inhibitor. The combination maintains viral suppression between injections and is used as maintenance therapy for patients who are already stable and well controlled on oral ART. Intramuscular formulations are used, and subcutaneous formulations have also been developed. The approved regimen is given by intramuscular injection; longer dosing intervals are being studied in clinical trials.

The overall result is therapy that is easier to take, has fewer side effects and fewer interactions, and supports a far longer life with HIV than was possible a generation ago.

How to recognise HIV treatment failure

HIV treatment failure has three components, clinical, immunological and virological, and virological failure is the decisive one. Dr. Rastogi Panda defines each:

• Clinical failure: the patient on ART develops a new opportunistic infection, or even a malignancy.
• Immunological failure: the CD4 count falls by 50% or more from its peak value, or fails to rise at all. A patient who started treatment with a count of 90 and still has 90 after two or three years has not responded.
• Virological failure: the decisive indicator. After at least six months of therapy, the viral load does not fall below the threshold, or, in a patient previously suppressed, it rises persistently. A viral load above 1,000 copies is the trigger for investigation.

Virological failure is what confirms the label. A falling CD4 count or a new infection should prompt the question; the viral load answers it.

A case of tuberculosis co-infection and missed doses

Dr. Rastogi Panda's most instructive case brought failure and tuberculosis together. A cricketer had been diagnosed with HIV three years earlier and started on TLE, a regimen of tenofovir, lamivudine and efavirenz. He presented with cough, fever and haemoptysis (coughing up blood). Asked whether he was taking his medicines, he admitted that he often missed doses during matches and practice sessions. His CD4 count had fallen from a baseline of 300 to 98, and his sputum was positive for Mycobacterium tuberculosis.

He met the clinical and immunological criteria for failure: pulmonary tuberculosis is a WHO stage 3 condition (clinical failure), and his CD4 count had fallen by more than half (immunological failure). His viral load needed to be checked to establish virological failure. The temptation is to switch regimens at once. Dr. Rastogi Panda did not:

1. She started anti-tuberculosis treatment.
2. She asked him to check his viral load and to continue the same antiretroviral regimen, this time taking it consistently.
3. She counselled him and his wife on the need to take every dose diligently.
4. She repeated the viral load after three months.

The viral load came down, and she continued the same therapy. The failure had been one of adherence, not of the drugs. Had the viral load stayed high, the next step would have been resistance testing where available, or a switch to second-line therapy.

Treating tuberculosis and HIV co-infection

Treating tuberculosis and HIV together means designing both regimens at once, because rifampicin, a cornerstone of anti-tuberculosis therapy, has major drug interactions with antiretroviral drugs. The two regimens cannot be chosen in isolation.

The co-infection is a major global burden. Tuberculosis is the leading cause of death among people living with HIV, and a significant proportion of tuberculosis deaths worldwide occur in people with HIV. HIV depletes the CD4 cells that contain tuberculosis, which makes infection easier to acquire and reactivate. Dr. Rastogi Panda described the co-infection as double trouble on three or four fronts: the disease itself, its clinical presentation and its treatment. How tuberculosis signals HIV, and how it is diagnosed in people with HIV, is covered in the complete guide.

Resistance testing and second-line ART

When an integrase-based first-line regimen fails, the patient moves to a second-line regimen built around a boosted protease inhibitor, ideally guided by resistance testing; after failure of an efavirenz-based regimen such as TLE, WHO recommends dolutegravir with an optimised NRTI backbone. The ideal is genotypic resistance testing, which reads the virus's genes for mutations that defeat specific drugs, both when therapy starts and when it appears to fail. Dr. Rastogi Panda acknowledged that many centres are not equipped for HIV resistance testing. In practice, when the viral load is rising, the CD4 count is falling and the patient has clinical features consistent with failure, the regimen is treated as failing and the patient is switched to second-line therapy.

In her practice, the second-line protease inhibitor, such as darunavir, is boosted with ritonavir. The integrase inhibitor is withdrawn and the boosted protease inhibitor takes its place.

The path towards a cure for HIV

A small number of people, about eight by Dr. Rastogi Panda's count, have been cured of HIV, all after stem cell transplants performed for blood cancers rather than for HIV itself. She was explicit that a cure for HIV is no longer a distant dream, and the therapeutic ladder now runs from single-pill regimens through long-acting injectable maintenance and two-drug therapy.

Transplantation is not a recognised treatment for HIV. In these patients, the transplant destroyed the patient's own marrow and replaced it with donor marrow, in most cases from a donor carrying a mutation in CCR5, the main receptor HIV uses to enter cells. Because the new marrow resisted the virus, it remained free of HIV RNA on sustained follow-up, and the patients were declared free of HIV.

Her own team has performed bone marrow transplants in two people living with HIV, one for Hodgkin lymphoma and one for acute myeloid leukaemia. The patient with acute myeloid leukaemia is surviving and doing well; the patient with Hodgkin lymphoma died recently of an opportunistic pneumonia. The procedure remains far from routine, but in her view it offers a genuine ray of hope.

The prevention side of the masterclass, including PrEP, PEP and the elimination of mother-to-child transmission, is set out in HIV prevention: PrEP, PEP and mother-to-child transmission. Doctors' questions on long-acting therapy and opportunistic infections are answered in the Live Discussion.