Introduction to combination therapy

Class	Description
RTIs or nukes	reverse transcriptase inhibitors – also called nucleoside or nucleotide analogues
NNRTIs	non-nucleoside reverse transcriptase inhibitors or non-nukes
PIs	protease inhibitors
EIs	entry inhibitors – CCR5 inhibitors are also entry inhibitors
INIs	integrase inhibitors

Class

Description

RTIs or nukes

reverse transcriptase inhibitors – also called nucleoside or nucleotide analogues

NNRTIs

non-nucleoside reverse transcriptase inhibitors or non-nukes

PIs

protease inhibitors

EIs

entry inhibitors – CCR5 inhibitors are also entry inhibitors

INIs

integrase inhibitors

HIV lifecycle – how drugs work in different ways

Each CD4 cell is used to produce hundreds of copies of HIV. Different drugs block different parts of the HIV lifecycle.

Life cycle of HIV in a CD4 cell

When to start combination therapy

UK current guidelines recommend starting treatment before your CD4 count falls below 200.
The next UK guidelines will probably recommend starting between 200 and 350 based on recent studies that show there are benefits to earlier treatment.
UK guidelines also recommend that a patient needs to be ready for treatment.

Choosing a combination

Guidelines recommend starting with either 2 nukes + an NNRTI or 2 nukes + a ritonavir-boosted PI.

First-line drugs by class

Combination nukes
Recommended: Truvada (tenofovir + FTC) Kivexa (abacavir + 3TC)	Alternative: Combivir (AZT + 3TC) Trizivir (abacavir + AZT + 3TC)
Single nukes
Recommended: abacavir (Ziagen) tenofovir (Viread) 3TC (lamivudine, Epivir) FTC (emtricitabine, Emtriva)	Alternative: AZT (zidovudine, Retrovir) ddI (didanosine, Videx) d4T (stavudine, Zerit)
NNRTIs
Recommended: efavirenz (Sustiva, Stocrin)	Alternative: nevirapine (Viramune)
PIs
Recommended: lopinavir/r (Kaletra) fosamprenavir/r (Telzir)	Alternative: atazanavir/r (Reyataz) saquinavir/r (Invirase) darunavir/r (Prezista) tipranavir/r (Aptivus) nelfinavir (Viracept)
EIs
Recommended: none currently in first line	Alternative: T-20 (Fuzeon) maraviroc (Celsentri)
INIs
Recommended: none currently in first line	Alternative: raltegravir (Isentress)

Combination nukes

Recommended:

Truvada (tenofovir + FTC)
Kivexa (abacavir + 3TC)

Alternative:

Combivir (AZT + 3TC)
Trizivir (abacavir + AZT + 3TC)

Single nukes

Recommended:

abacavir (Ziagen)
tenofovir (Viread)
3TC (lamivudine, Epivir)
FTC (emtricitabine, Emtriva)

Alternative:

AZT (zidovudine, Retrovir)
ddI (didanosine, Videx)
d4T (stavudine, Zerit)

NNRTIs

Recommended:

efavirenz (Sustiva, Stocrin)

Alternative:

nevirapine (Viramune)

PIs

Recommended:

lopinavir/r (Kaletra)
fosamprenavir/r (Telzir)

Alternative:

atazanavir/r (Reyataz)
saquinavir/r (Invirase)
darunavir/r (Prezista)
tipranavir/r (Aptivus)
nelfinavir (Viracept)

EIs

Recommended:

none currently in first line

Alternative:

T-20 (Fuzeon)
maraviroc (Celsentri)

INIs

Recommended:

none currently in first line

Alternative:

raltegravir (Isentress)

Currently recommended for people with drug resistance.

Nukes that dont mix

Nuke pair	When not to use
AZT and d4T	At any time
FTC and 3TC	At any time
ddI and tenofovir	Especially with an NNRTI
abacavir and tenofovir	In a 3-drug combo until an interaction is explained
d4T and ddI	Never during pregnancy
Triple-nuke combinations	Only two combinations – AZT + 3TC + abacavir or AZT + 3TC + tenofovir – can be used. Others have a high risk of failure

Nuke pair

When not to use

AZT and d4T

At any time

FTC and 3TC

At any time

ddI and tenofovir

Especially with an NNRTI

abacavir and tenofovir

In a 3-drug combo until an interaction is explained

d4T and ddI

Never during pregnancy

Triple-nuke combinations

Only two combinations – AZT + 3TC + abacavir or AZT + 3TC + tenofovir – can be used. Others have a high risk of failure

Most commonly used first line combinations

Each option is used with EITHER Truvada (tenofovir + FTC) OR Kivexa (abacavir + 3TC).

Drug name and comments	Side effects	Other notes
Efavirenz (Sustiva, Stocrin) Efavirenz is widely recommended as part of a first line therapy. It is one pill, oncedaily. Side effects, which can be significant, usually reduce after the first few weeks.	Main side effects are sleep disturbance (including nightmares), mood disturbance (including anxiety and depression) rash, liver toxicity and lipid changes. About 20% people switch to another drug over the first year.	Efavirenz should not be used during pregnancy or by women trying to conceive a baby.
Nevirapine (Viramune) Nevirapine is an alternative to efavirenz, but has a small higher risk of serious side effects compared to efavirenz. Nevirapine is started at one tablet a day for the first two weeks, and then one tablet twice-daily.	Main side effects are rash and liver toxicity. These only occur in the first 6-8 weeks. Any low level rash should be taken seriously. Serious rash can be fatal. If you still have a rash after the first two weeks do not increase the dose but see your doctor.	Women with a CD4 count over 250 and men with a count over 400 should not start with nevirapine.
Lopinavir/r (Kaletra) Kaletra is recommended as the preferred protease inhibitor. It is a twice-daily drug that includes ritonavir inside the same pill.	Main side effects are changes in lipids (blood fat), lipodystrophy (fat accumulation) which should be routinely monitored, and diarrhoea.	There is a low risk of resistance.
Atazanavir/r (Reyataz) Atazanavir/r is not currently approved in Europe as first-line treatment, but it is still widely used, because it is dosed once-daily and generally easy to tolerate.	Main side effects are yellowing eyes or skin in 10% of patients, relating to increased levels of bilirubin. This is only a clinical problem when total bilirubin levels increase to 60-70 mmol/L. Lipids can increase due to the boosting dose of ritonavir.	Taken with a separate dose of ritonavir (/r), unless you have high drug levels.
Fosamprenavir/r (Telzir) In studies fosamprenavir/r had similar results to Kaletra, but is less commonly used.	Side effects, including diarrhoea and lipids are similar to Kaletra.	Taken with a separate dose of ritonavir (/r).
Saquinavir/r (Invirase) Saquinavir/r has shown similar results to Kaletra. There is less comparative data to Kaletra than for fosamprenavir/r.	Side effects, including diarrhoea and lipds are similar to Kaletra. May have a lesser effect on trigliceride levels.	Taken with a separate dose of ritonavir (/r).

Drug name and comments

Side effects

Other notes

Efavirenz (Sustiva, Stocrin)
Efavirenz is widely recommended as part of a first line therapy. It is one pill, oncedaily. Side effects, which can be significant, usually reduce after the first few weeks.

Main side effects are sleep disturbance (including nightmares), mood disturbance (including anxiety and depression) rash, liver toxicity and lipid changes. About 20% people switch to another drug over the first year.

Efavirenz should not be used during pregnancy or by women trying to conceive a baby.

Nevirapine (Viramune)
Nevirapine is an alternative to efavirenz, but has a small higher risk of serious side effects compared to efavirenz. Nevirapine is started at one tablet a day for the first two weeks, and then one tablet twice-daily.

Main side effects are rash and liver toxicity. These only occur in the first 6-8 weeks. Any low level rash should be taken seriously. Serious rash can be fatal. If you still have a rash after the first two weeks do not increase the dose but see your doctor.

Women with a CD4 count over 250 and men with a count over 400 should not start with nevirapine.

Lopinavir/r (Kaletra)
Kaletra is recommended as the preferred protease inhibitor. It is a twice-daily drug that includes ritonavir inside the same pill.

Main side effects are changes in lipids (blood fat), lipodystrophy (fat accumulation) which should be routinely monitored, and diarrhoea.

There is a low risk of resistance.

Atazanavir/r (Reyataz)
Atazanavir/r is not currently approved in Europe as first-line treatment, but it is still widely used, because it is dosed once-daily and generally easy to tolerate.

Main side effects are yellowing eyes or skin in 10% of patients, relating to increased levels of bilirubin. This is only a clinical problem when total bilirubin levels increase to 60-70 mmol/L. Lipids can increase due to the boosting dose of ritonavir.

Taken with a separate dose of ritonavir (/r), unless you have high drug levels.

Fosamprenavir/r (Telzir)
In studies fosamprenavir/r had similar results to Kaletra, but is less commonly used.

Side effects, including diarrhoea and lipids are similar to Kaletra.

Taken with a separate dose of ritonavir (/r).

Saquinavir/r (Invirase)
Saquinavir/r has shown similar results to Kaletra. There is less comparative data to Kaletra than for fosamprenavir/r.

Side effects, including diarrhoea and lipds are similar to Kaletra. May have a lesser effect on trigliceride levels.

Taken with a separate dose of ritonavir (/r).

How to check treatment is working

Regular monitoring, using blood tests, will check that the drugs continue to work.

Viral load tests measure the amount of HIV in your blood.
Results are given as copies/mL.
CD4 tests measure how strong your immune system is.
Results are given as cells/mm³.

CD4 count and risk of becoming ill

While your CD4 count is above 300, you still have a good immune system. Below 300, you are at a higher risk of infections that cause diarrhoea and weight loss.
If your CD4 count falls below 200, your risk of developing a pneumonia called PCP increases. Below 100, your risk of serious illnesses increases even further.

The importance of different viral load levels when on treatment

Less than 50 (<50 copies/mL)
So little HIV is produced that resistance is unlikely to develop to your combination. So long as you continue taking the drugs carefully, you could use them for many years.
Between 50 and 500 (>50 and <500 copies/mL)
This is not low enough to stop resistance. At some point, as resistance becomes more extensive, the drugs will stop working and your viral load will rebound much higher.
Over 500 (>500 copies/mL)
If you continue to take treatment while your viral load is detectable (and not still falling) resistance will mean you can only use your combination for a limited time.

Resistance – drug levels and missing doses

Drug levels with good adherence
Drug doses are calculated so that average drug levels are high enough to be active against HIV without risking resistance – 24 hours a day – and low enough to minimise the risk of side effects.

Regular doses avoids low drug levels which can lead to resistance

A missed or late dose increases the risk of resistance
Missing or being late with a drug lets the drug levels fall to a level where resistance can develop. The more often you are late or miss a dose, the greater the chance this will occur.

Missed does = low drug level = rislk of resistance

CD4 count and equivalent CD4% for babies and children by HIV disease category

HIV disease category	CD4%	CD4 0-12 months old	CD4 1-5 years old	CD4 6-12 years old
Category 1 - no damage	25% or over	over 1,500	over 1,000	over 500
Category 2 - moderate	15-24%	750-1,500	500-1,000	200-500
Category3 - severe	less than 15%	less than 750	less than 500	less than 200

HIV disease category

CD4%

CD4
0-12 months old

CD4
1-5 years old

CD4
6-12 years old

Category 1 - no damage

25% or over

over 1,500

over 1,000

over 500

Category 2 - moderate

15-24%

750-1,500

500-1,000

200-500

Category3 - severe

less than 15%

less than 750

less than 500

less than 200

This is the web edition of the i-Base guide Introduction to combination therapy. This guide is available in UK clinics. You can order free printed copies or download a PDF version (516 Kb). Translations. Authors and credits. Glossary. Full section index.

Decisions relating to your treatment should always be taken in consultation with your doctor. Information in this guide is intended to support those discussions.

Tables and diagrams

Types of HIV drugs

HIV lifecycle – how drugs work in different ways

When to start combination therapy

Choosing a combination

First-line drugs by class

Nukes that dont mix

Most commonly used first line combinations

How to check treatment is working

CD4 count and risk of becoming ill

The importance of different viral load levels when on treatment

Resistance – drug levels and missing doses

CD4 count and equivalent CD4% for babies and children by HIV disease category