Side-effects

One consideration that applies both to PEP and to PrEP is that when antiretroviral drugs are given to people who are HIV-negative, the level of toxicity that is acceptable is lower than when drugs are used to treat a life-threatening illness.

Many countries do not recommend three-drug regimens, due to their side-effects and cost. Many countries use two NRTIs except in very high-risk exposures or when there is evidence that the transmitted virus could be drug-resistant.

A poster at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in 2006¹ discussed the tolerability of PEP regimens given at nine hospitals in France. The regimens compared were:

• AZT/3TC (Combivir) plus nelfinavir (Viracept)
• Combivir plus lopinavir/ritonavir (Kaletra)
• Combivir plus tenofovir
• Tenofovir/3TC plus atazanavir (Reyataz)/ritonavir (Norvir).

The regimen containing nelfinavir was significantly less well tolerated, with 34.5% of patients discontinuing a 28-day course of PEP due to side-effects, compared with an average of 20% on the other regimens.

Commentators at the poster session said they had found AZT-free regimens were better tolerated; questioned the usefulness of Kaletra due to its poor genital penetration; and aired the ever-controversial topic (in PEP terms) of whether to provide two or three drugs.

When in 2005 an HIV clinic in Boston² switched the PEP combination it prescribed from Combivir to Truvada they found lower rates of side-effects.

A survey of occupational antiretroviral PEP among health workers in Canada³ uncovered a major hidden cost. Time off work due to side-effects of the drugs cost the health service as much as providing the drugs for the treatment. This time off work appears to have doubled, from an average of 7.0 days to 15.8 days in the year 2000, when the protease inhibitor nelfinavir was added to the regimen (previously d4T plus 3TC).

Since guidelines have changed the recommended PEP regimens, however, side-effects have become much less burdensome. One study presented at the 2010 BHIVA/BASHH conference⁴ showed that following a change in the recommended PEP regimen to tenofovir/FTC/boosted lopinavir (Truvada/Kaletra), drug side-effects and interactions have become rare. In this study 140 patients took Truvada/Kaletra and there was only one patient, a heavy drinker, whose PEP had to be changed (by stopping his Kaletra in the fourth week) because he had a significant rise in enzymes indicating liver damage. Nine other patients had mild disturbances in liver and kidney function but these resolved themselves. No patient who had abnormal liver or kidney function tests at baseline developed PEP-specific toxicity.

The researchers suggested that it may therefore be unnecessary to bring in most patients for monitoring of drug levels and liver and kidney function during their four weeks on PEP unless they have significantly abnormal baseline tests or the potential for drug interactions.

Another French study⁵ was based on 249 participants who took PEP between November 2006 and June 2008 in 10 French hospitals, mostly (82%) after sexual exposure. Tolerability could be evaluated in 188 cases. In 22 cases, PEP was discontinued for adverse effects before day 28, including two cases of skin rash related to tenofovir and one case of kidney stones ascribed to lopinavir. Two-thirds (166) of participants completed the 28 days of PEP with tolerability judged as good in 96 (58%) individuals. Among everyone who experienced at least one side-effect, 78% reported diarrhoea, 78% weakness, and 59% nausea and/or vomiting.

Compared to previous studies, the drop-out rate due to side-effects appeared to be significantly lower in people taking Truvada/Kaletra tablets than in people taking either AZT/3TC/nelfinavir, AZT/3TC/Kaletra soft-gel capsules, or tenofovir/3TC/atazanavir/ritonavir.