Reviews in Medical Virology Rev. Med. Virol. 9: 1–2 (1999)

Why is the Efficacy of HAARTso Durable?

The availability of combinations of anti-retroviral drugs(highly active anti-retroviral therapy; HAART) haspotently controlled HIV replication. This has translateddirectly into clinical benefits with reduced disease due toopportunistic infection and opportunistic tumours whichpreviously caused substantial disease once HIV hadrendered the patient profoundly immunocompromised.1

Clearly, the damaged immune system has remarkableplasticity and can recover function, even when HAART isgiven late in the disease process.

Given the ability of HIV to replicate rapidly and selectquasispecies2 able to escape from control of HAART,many investigators expected that patients would benefitfrom a ‘honeymoon’ period but then progressively suc-comb to opportunistic infections and tumours once againas resistant viruses damaged the immune system. Cer-tainly, clinicians caring for AIDS patients describe‘HAART failure’, but this phrase is used vaguely andwithout definition. Some use the term to describe theirdisappointment that the HIV viral load has not declinedby as much as hoped, and/or that the CD4 count has notincreased as much as expected. Others use the term whenthe HIV viral load declines to a low or undetectable levelbut subsequently becomes detectable again, despite con-tinuing therapy. Of course, patients may fail to respondto treatment if they fail to take the prescribed medication,and compliance is a major problem for the complicatedregimes of HAART. However, once non-compliantpatients have been exluded, and irrespective of the detailsof the drugs prescribed, in most cases of ‘HAART failure’such patients continue to derive clinical benefit fromongoing HAART therapy in spite of the disappointingresults of laboratory tests. Perhaps we should reserve theterm ‘HAART failure’ for those who develop progressive,new AIDS-defining conditions despite continuingtherapy. Meanwhile, the relative rarity of such clinicalprogression despite disappointing laboratory test resultsrequires explanation.

One possibility is that the direct measurement of HIVRNA levels may give the correct numerical values butnot represent fully infectious virus. For example, HAARTcombinations with protease inhibitors may allow HIV

CCC 1052–9276/99/010001–02 $17.50Copyright ? 1999 John Wiley & Sons, Ltd.

virions to be produced which contain RNA but arenon-infectious by virtue of inhibition of protease-mediated cleavage of capsid proteins to their matureforms (reviewed in3).

Second, the virions may be infectious but have reducedvirulence. For example, quasispecies with resistance toone or more of the HAART components may surviveand propagate but at the expense of losing some potencyof replication and/or pathogenicity.2

Third, the virions may be infectious and fully virulentbut constantly boost the immune system to control someof their pathogenic effects. For example, the surfaceglycoproteins of HIV SU gene are cleaved not by thevirus-encoded protease but by a cellular enzyme. Thus,continuing HAART therapy might allow the productionof virions which repeatedly present authentic SUepitopes to the immune system. By boosting the affinityof antibodies which can neutralise virus, including post-adsorption entry,4 pathogenicity could be reduced with-out declaring the benefits through observed CD4 countchanges.

Fourth, it is clear that the immune reconstitution whichresults from HAART can reduce the replication ofopportunistic infections which would otherwise causeopportunistic diseases. Many such opportunistic infec-tions have, in the past, been implicated as possible agentsable to increase the pathogenic effects of HIV (reviewedin5). Such a ‘co-factor’ phenomenon has been controver-sial in the past but is now becoming accepted in the caseof HSV-2/HIV interactions.6 If co-factor viruses increasedHIV pathogenicity prior to HAART, then their suppres-sion back into latency by HAART-induced immunereconstitution could be responsible for some of theclinical benefits seen with HAART.

Finally, the potent drugs employed in HAARTregimes could have unanticipated effects on cellularmetabolism which indirectly affect HIV pathogenicity.For example, the lipodystrophy caused by chronic use ofprotease inhibitors has been attributed to inhibition ofmammalian enzymes whose natural function is to pro-duce 9-cis-retinoic acid (9cRA).7 Receptors for 9cRA areubiquitous and the effects of retinoic acid therapy on

2 EDITORIAL

virus infections, including HIV, are complex (reviewedin8). Nevertheless, since retinoic acid can alter thedifferentiation of macrophages, an important cellulartarget for HIV replication, it is possible that the patho-genicity of HIV could be affected indirectly by thereduced availability of 9cRA.

Given all of these possibilities, it is not clear why theeffect of HAART has been so durable; as a result, it isimpossible to predict when the effects will wane. Prospec-tive studies are required to differentiate between thepossibilities discussed and will need to measure qualita-tive aspects of HIV fitness. Comparison of the long-termeffects of HAART regimens containing nucleosidereverse transcriptase inhibitors plus either a proteaseinhibitor or a non-nucleoside reverse transcriptase inhibi-tor could be informative. By prospectively followingpatients, the decline in function of immune parametersmay provide some insights into which effector mecha-nisms are important and may define how much of theimmune system (both in terms of quantity and quality ofresponse) is required to keep each opportunistic infectionand opportunistic tumour at bay. In the meantime,clinicians should beware of changing drugs based solelyon the results of laboratory tests of viral load or of CD4count.

P. D. Griffiths

Copyright ? 1999 John Wiley & Sons, Ltd.

REFERENCES1. Palella, F. J., Delaney, K. M., Moorman, A. C. et al.

(1998). Declining morbidity and mortality amongpatients with advanced human immunodeficiencyvirus infection. N. Engl. J. Med.. 338, 853–860.

2. Domingo, E., Menendez-Arias, L. and Holland, J. J.(1997). RNA virus fitness. Rev. Med. Virol. 7, 87–96.

3. Jones, I. and Morikawa, Y. (1998). The molecular basisof HIV capsid assembly. Rev. Med. Virol. 8, 87–95.

4. Dimmock, N. J. (1995). Update on the neutralisation ofanimal viruses. Rev. Med. Virol. 5, 165–179.

5. Griffiths, P. D. (1998). Studies to further define viralco-factors for human immunodeficiency virus. J. Gen.Virol. 79, 213–220.

6. Schacker, T., Ryncarz, A. J., Goddard, J., Diem, K.,Shughnessy, M. and Corey, L. (1998). Frequent recov-ery of HIV-1 from genital herpes simplex virus lesionin HIV-1-infected men. JAMA. 280, 61–66.

7. Carr, A. Samaras, K. Chisholm, D. J. and Cooper, D. A.(1998). Pathogenesis of HIV-1 protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia,and insulin resistance. Lancet 351, 1881–1883.

8. Ghazal, P., LeBlanc, J. F. and Angulo, A. (1997).Vitamin A regulation of viral growth. Rev. Med. Virol.7, 21–34.

Rev. Med. Virol. 9: 1–2 (1999)