11 Basics of Antiretroviral Therapy

Alison Grant 31/8/18

11.1 NRTIs

Initial plan was to give AZT alone, in 1987. That was the first of the NRTI agents. They inhibit reverse transcriptase.

There are now loads of reverse transcriptase inhibitors.

The problem with them is they inhibit mitochondrial enzymes also, causing mitochondrial toxicity (lipoatrophy, peripheral neuropathy, pancreatitis, lactic acidosis)

New NRTI’s are well tolerated.

3TC/FTC class of NRTI’s are well tolerated, also work against Hep B. Problem is it also gets resistance quickly.

ABC (abacavir) causes hypersensitivity, in countries with HLA B 5701 type, this can be life threatening. Tested for in high income, not in low income. Avoided in patients w hhigh baseline viral load, less potent drug so less useful.

TDF (tenofovir) is well tolerated, and effective against Hep B also, but can cause renal tubular disease

TAF (coming soon, tenofovir alafenamide), this is like tenofovir, bbut causes less renal tubular acidosis. Problem is more expensive and drug interactions

In 1994 concorde showed that AZT monotherapy was not so useful in the longer term. This was due to longer term mutations, resulting in AZT becoming inactive

In 1996, more NRTI’s become available. DDI (didanosine) and zalcitabine. Dual therapy was shown to be more effective than monotherapy.

11.2 Protease Inhibitors

These prevent the cell chopping up RNA at the end of the viral cycle within the cell. These were “designer drugs”, to inhibit protease.

These were tested in 1996, looking at effect on viral load. Indinavir was first to be tested. Much more effective in reducing viral load than NRTI dual therapy.

Then HAART (highly active antirretroviral therapy) came along. Two NRTI’s plus indinavir. Big difference in risk of death in the short term.

• Darunavir
• Atazanavir
• Ritonavir (is used as a booster) - tastes absoulety foul, but was one of the earliest, but comes as liquid
• Lopinavir (lop + rit = kaletra)

Protease inhibitors have major drug drug interactions (ritonavir is the worst for it). They act on cytochrome p450. If you give a tiny dose of ritonavir, it inhibits the metabolism of other protease inhibitors, allowing you to give smaller doses of them.

All PI’s cause gi side effects (diarrhoea). But less with newer ones. They increase cholesterol and insulin resistance.

Darunavir - once daily Atazanavir - used quite a lot, fine for cholesterol, but does give you gilberts, so you will see a raised bilirubin, and kidney stones. You cannot take with PPIs Lopinavir - widely used as second line treatment, but does prolong QT

11.3 NNRTIs

First of these was nevirapine. In 1998 was shown with 2 NRTIs to improve proportion of people with supressed viral load. 1998 was able to measure viral load routinely for first time.

First gen:

• Nevirapine
• Efavirenz

Second gen:

• Etravirine
• Rilpivirine

They act in a diff way to NRTIs, so can be added on.

As a class, they generally cause, rash, hypersensitivity. It doesn’t take much to see resistance in them. HIV 2 has intrinsic resistance to NNRTIs

Efavirenz, extremely widely used. Long half life, can be given once a day. Hepatitis and rash are rare with it (but possible). It’s main SE’s are neuropsychiatric (vivid dreams, dizziness, sleepy). It gets taken as a recreational drug in South Africa. It makes your anxiety better!

Rilpivarine, will likely become one of the new injectable ARVs

11.4 Continue Story

By late 1990s, the backbone of treatment was triple therapy. 2 NRTIs plus anchor drug of PI, or NNRTI. Originally HAART meant with a PI. But could also mean combination ART.

The problem was that it had significant cost. Multiple drug interactions with multiple side effects.

Most of the subsequent changes have been done to make the treatment more tolerable and easier.

One of the first thing was to compare PI versus NNRTI. NNRTI seemed to do better in side effects and viral load. So in early 2000’s this became a standard: Atripla (TDF/FTC/EFV). One pill, once a day.

There’s now a few of these one pill. Once a day.

11.5 INSTI

Integrase inhibitors.

Inhibiting the integration of viral DNA with host DNA

First was raltegravir. Problem was 2x daily dose.

As a class, they’ve got v well tolerated.

Dolutegravir. This is the big new thing. Was hyped +++ on release. High genetic barrier to resistance. You can give with rifampicin.

But, in May, an observational study in Botswana, babies with neural tube defects were born to mothers taking Dolutegravir (with small numbers in the study). Causing caution, but may be a chance finding, statistically. Prior to this study, dolutegravir was going to be the new “anchor” drug. We’ll have to watch and see.

11.6 Other ARTs

11.6.1 Entry Inhibitors

11.6.1.1 Fusion Inhibitors

Stop the virus attaching

Only could be prescribed sub-cut. Hardly ever used.

11.6.1.2 CCR 5 receptors

Only work for certain viruses

11.7 What to avoid

SEE SLIDES ON MOODLE “WHAT TO AVOID IN AN ART REGIMEN”

11.8 Aims of treatment

When do we start? Info suggests starting treatment sooner and sooner. SE’s less, treatment benefits high.

We’re moving towards: Test then start in all cases.

WHO recommends treating all cases. Possibly prioritise higher WHO grades.

In practice we use few treatment regimens. To simplify monitoring, simplify supply chain.

The standard first line regimen would be atripla. But there’s a lot of efavirenz resistance, to maybe need switch from efaviranz,

In london what we give is either: Kivexa or Truvada with a third drug, Raltegravir or Efarvirenz, Darunavir. Darunavir is more usefel for when you’re worried about poor adherence, as it’s hard to get resistnace to it.

In tanzania, truvada plus efavirenz In uganda, atripla