Antiretroviral Therapy Today
In late 2007, twenty antiretrovirals are available on the European market, with a further three drugs approaching official release in early 2008. In the last 10 years, by excluding some pharmaceutical remake and dual or triple drug co-formulations of existing drugs, the mean number of new antiretrovirals per year has been 1.5.
Today, four drug classes are available (N/NtRTIs, NNR- TIs, PIs, entry inhibitors), and a fifth (integrase inhibitors) is about to make its entry in the anti-HIV pharmacopea. Newer drugs classifiable in the existing classes and new classes are also in the pipeline (maturation inhibitors, monoclonal antibodies as entry inhibitors), thus testifying of the exciting liveliness of this pharmaceutical sector, probably the most active branch of pharmaceutical research in these times.In the years following the first introduction of HAART, the therapeutic strategies underwent several changes on the basis of the new knowledge resulting from clinical evidence and according to the properties of the numerous new drugs that have been released over time. Therapeutic guidelines delivered by national and supranational health authorities (e.g. DHHS in USA and BHIVA in UK) are continuously updated in order to provide the best available indications for the overall management of HIV infection [44, 45].
The basic therapeutic potential of antiretroviral therapy today is that of providing significant inhibition of viral replication and then, as a result of the latter, recovery of CD4+ T-lymphocytes. This translates into clinical recovery in those who are symptomatic and in a condition of clinical stability for patients who begin their treatment while still in the asymptomatic stage. The response rate, which may vary according to numerous factors, may well be over 75% in patients starting HAART, and today numerous alternative options are available for those who do not respond to their first regimen.
The most atypical and thorny aspect of HAART is that it must be administered for life. HIV infection is the only infectious disease requiring permanent therapy, as treatment interruption is followed by resumed viral replication, immunological impairment and progressive clinical deterioration, that is to say that HIV infection resumes its natural course. The only analogy may be that of chronic hepatitis B infection, for which, today, continuous suppressive treatment is also being advised [46].The clinical demand has been changing over time as a consequence of different problems that arose in clinical practice. In the first years following the introduction of HAART, it soon became apparent that HIV was able to change its susceptibility to antiretrovirals and to become drug-resistant in a classic Darwinian way. By applying methods of molecular biology, it was possible to identify genotypic patterns of viral isolates that were correspondent to distinct phenomena of drug resistance. While In Vitro systems for testing viral sensitivity to antiretrovirals (phenotyping) were also developed, viral genotyping was found to be the most reliable and practical method for guiding antiretroviral selection in the case of resistant infections and today it remains the reference method [47].
A fundamental change in antiretroviral therapy took place when clinical pharmacology studies provided the means to overcome and prevent viral resistance. Among the first PIs released into the market, Ritonavir (RTV, which was subsequently abandoned as pure antiretroviral) was found to display remarkable properties in enhancing the pharmacokinetic (PK) exposure of other PI [48]. Through its interference with the isoenzyme CYP3A4 of the cytochrome P 450 system in the intestine and liver microsomes, RTV (at a daily dosage well lower than that recommended for its use as antiretroviral) was found to be able to increase PIs absorption and to decrease their metabolism, thus eventually leading to PK exposure of the co-administered PI which was up to 3 logs10 higher than in the case of treatment without RTV.
Such enhanced PK exposure led to the ability of RTV/PI-based treatments to overcome, to some significant extent, the pre-existing resistance selected by regimens containing a single PI, thus determining successful re-suppression of viral replication in patients who underwent virological failure with a single PI-based therapy. Furthermore, in the following years, it became apparent that the use of RTV/PI-based therapy was also able to almost totally avoid the selection of resistance when administered as first-line treatment in treatment-naive patients [49]. The effect of this enhanced PK exposure on resistance prevention was found to also include the drugs co-administered with RTV/PI-based regimens, thus providing a benefit, in terms of long-term perspective, which goes far beyond the class of PIs and involves the entire pharmaceutical armamentarium we rely upon today for treating HIV infection. It must be stressed that the confidence we have today in the possibility to find a therapeutic solution for almost all individual patient conditions (e.g. resistance, intolerance, drug-drug interactions, pregnancy, organ failure, etc.) is largely based on the knowledge that RTV-boosted PI-based regimens will provide a concrete chance of therapeutic response in the vast majority of patients, unless very extensive resistance has been selected in the past. In this regard, it is worth noting that the process of multiple drug resistance selection resulting from the use of suboptimal regimens (which took place until the concept of boosting PI-based therapy with low- dose RTV was fully translated into large- scale use) has now come to its end, at least in the western world. This is to say that the use of RTV-boosted PI therapy does not generate the multiple resistance patterns selected by a single PI therapy any longer; and, thus, the size of the HIV-infected population carrying multiple drug resistance should not increase to any significant extent in the future [50].Most of currently administered HAART regimens consist of two drugs belonging to the N/NtRTIs class (the so called “N/NtRTIs backbone”) and a third drug to be selected among PIs or NNRTIs.
When administered to patients in a treatment-naive status, these regimens have repeatedly been proven to guarantee a long-term immunovi- rological and clinical benefit-provided they are taken regularly by the patients and no specific interferences are present. In the case of patients who are not eligible for these first-line recommended options because of prior resistance selection, a number of alternatives are available, both within the class of PIs (in the near future also in the class of NNRTIs) and in other newly developed drug classes [44, 45].Although viral resistance is not the only problem in this therapeutic area, it is nevertheless the one that may definitively compromise the use of a drug class. While PIs are now recognized to be the drug class less vulnerable to resistance selection (in the RTV-boosted version), N/NtRTIs, NNRTIs and Enfuvirtide (the only entry inhibitor so far available) display various degrees of weakness in terms of genetic barrier. The term genetic barrier substantially indicates the number of mutations required to make HIV resistant to a drug or a drug class. The higher the number of mutations required to determine resistance, the stronger the genetic barrier. With the exception of PIs in association with RTV as a booster, for most of the other drugs, a single mutation (such as even a short exposure) may be sufficient to select for a drug-resistant infection. Considering that cross-resistance among members of the same class is rather common, attention is being increasingly paid to the best sequential strategy to be adopted in planning antiretroviral therapy. What has been learned after years of antiretroviral therapy is that the same principles applied almost 60 years ago in the multi-drug treatment of tuberculosis are also valid for antiretroviral therapy [51]. In other words, once resistance has developed and we have to face treatment failure, no single new active drug should be added to a failing regimen, since selection of resistant mutants will determine the emergence of virions which are also resistant to the newly introduced drug.
In all clinical trials carried out to evaluate the effectiveness of new antiretrovirals, the best performances were seen when at least another component of the therapeutic regimen (further to the new experimental drug) was fully active against the virus. With only a single drug being active in any given regimen, the usual therapeutic result is that of a transient immunovirological response (often not complete) followed by a new therapeutic failure. As a consequence, in case of multi-drug failure, the best strategy is to select at least two active components to be included in the new regimen [52].Side effects, both short and long-term, are another important issue in antiretroviral therapy. There are a number of drug-specific untoward effects to which patients are variably vulnerable [53]. Gastrointestinal reactions and hypertriglyceridaemia are more common with PIs, and among PIs there are effects like jaundice or nephrolythiasis which are attributable to specific drugs (respectively Atazanavir, ATV, and Indinavir, IDV). In this drug class, some differentiation is also worth making between ATV, Tipranavir (TPV) and the rest of the class in terms of disturbances of glucose homeostasis and decrease in insulin sensitivity; the former two, which do not interfere with the cellular receptor GLUT-4, are less prone to determine alterations in this setting. Cutaneous rash is more common with NNRTIs than with PIs, and neuropsychiatric disturbances (especially in the first weeks of treatment) are more common with Efavirenz (EFV) than with any other antiretroviral. Some degree of liver toxicity is attributed to NNRTIs, and their use should be cautious in case of co-existing viral hepatitis. On the side of the current most common “backbone” of HAART (N/NtRTIs), there are some specific reactions in the case of abacavir (ABV, genetically determined vulnerability for developing severe inflammatory reactions), tenofovir (TDF, reversible renal failure with concurrent factors), zidovudine (AZT, anaemia, lipoathro- phy), Didanosine (peripheral neuropathy, pancreatitis) and stavudine (d4T, lipoathro- phy), while the two citidine analogues lamivudine (3TC) and emtricitabine (FTC) are by far the best tolerated drugs in this class [54].
The outlook of side effects should also be analysed in longer terms such as in years of continuous treatment. In this perspective, complex pictures consisting of various degrees of metabolic and morphologic alterations are known to occur in recipients of antiretroviral therapy. From the metabolic side, disturbances in the glucose and lipid profiles are rather common and may form the basis for interpreting the higher incidence of cardiovascular events recorded in HAART intakers as compared to the age- matched population. While a small classspecific responsibility seems today to be attributable to PIs as compared to NNRTIs in the increased cardiovascular risk, many other concurrent factors should also be considered in this specific context, since traditional risk factors, like smoking, are also heavily represented in the HIV-infected population [55]. The other side of the coin, however, shows how a higher cardiovascular risk is also measurable in those with lower CD4+ cell counts, which means that in any case, the successful use of HAART is well favourable also in this specific regard [56].The development of lipodystrophic syndromes (altered distribution of body fat), which have ambiguous links with the metabolic disturbances, is more likely to result from regimens containing d4T or, to a lesser extent, AZT, while the responsibility of other drugs is still sub judice. A recent ACTG trial (ACTG 5142) has actually capsized the belief that lipoathrophy was more common among PIs intakers as compared to NNRTIs; the results showed how the incidence of lipoathrophy was significantly higher in patients taking EFV as compared to those receiving lopinavir/RTV (LPV/r), regardless of the companion drugs also administered [57].
An additional point to consider in the long-term perspective is that of the incidence of non HIV-related diseases in the HIV-infected population. As said for the increased risk of cardiovascular events with lower CD4+ cell counts, the same applies for other conditions like renal failure, non- opportunistic infections and malignancies. This means that, in order to lower the risk of such occurrences over time as far as possible, our immunological target in antiretroviral therapy should be set at levels higher than 350 cells/pl. In the ongoing debate on the best therapeutic strategy for achieving the most convenient balance between treatment efficacy and side effects, this information certainly adds more weight on the side of the favourable effects of antiretroviral therapy [56].