An overview of the conference

1 February 2003. Related: Conference reports, Antiretrovirals, Lipodystrophy and metabolic complications, HIV 6th Glasgow 2002.

Graeme Moyle, HIVandHepatitis.com

The 6th International Congress on Drug Therapy in HIV infection followed the format of the previous meetings, consisting predominantly of oral plenary sessions with ‘experts’ summarising the current state of the art in treatment-related issues, a small number of oral presentations of new data and a poster session extending to around 300 posters of data predominantly derived from European treatment centres.

Viral load testing

Over the evolution of viral load testing the lower limit of detection has declined from 10,000 copies/ml with the first Chiron assay, to 4-500 copies/ml, and most recently to the standard of less than 50 copies/ml. Studies such as the INCAS study demonstrated that there were benefits in terms of treatment durability in achieving suppression below 20 copies/ml relative to individuals who achieved suppression below 500 copies but remained above 20 copies/ml.

Evidence from studies examining viral evolution or LTR circles has indicated that ongoing viral replication occurs in a substantial subset of individuals who have viral loads repeatedly below 50 copies/ml. This begs the question as to whether there are further returns in terms of treatment durability or improved immune reconstitution in individuals who suppress viral load below five copies/ml (ie a further logarithm below the current cut-off).

This idea was evaluated in individuals naïve to antiretroviral therapy who initiated on a triple therapy regimen with Zerit (stavudine, d4T), Epivir (lamivudine, 3TC) and Kaletra (Lopinavir/ritonavir). The study used a modified Amplicor assay, which had a limit of quantitation of less than three copies/ml. Samples from patients with viral loads less than 50 copies/ml at which 24, 48 and 72 were analysed using this assay and the outcome of these patients after four years of follow-up was correlated with suppression.

The study included 100 individuals with a median baseline viral load of 4.8 log copies/ml and a median CD4 count of 326 cells/mm3. By intention to treat analysis at week 204, 71% of patients had a viral load less than 400 copies and 70% had a viral load less than 50 copies/ml, by on treatment analysis the proportions being 99% and 97%, respectively. Fifteen individuals met criteria of virological failure defined as two consecutive samples with viral load values > 400 copies/ml on therapy.

Patients who commenced therapy with viral load less than 100,000 copies or CD4 count greater than 200 cells/mm3 were more likely to achieve at least one viral load value <3 copies/ml. Stratification by baseline viral load above and below 100,000 copies/ml, 37% versus 72% of individuals achieved at least one viral load <3 copies/ ml and for CD4 cell count below and above of 200 cells/mm3, 37% and 67% of patients, respectively, achieved at least one <3 copies/ml viral load value.

Patients who achieved a viral load >3 copies/ml were no less likely to experience virological failure than those who had at least one or indeed multiple viral load values <3 copies/ml. Additionally, time to loss of virological response did not differ between individuals who achieved and those who did not achieve a virological response to <3 copies/ml.

These data would suggest that pushing the limits of detection of viral load assays lower than those currently available provides no greater return in estimating the likely durability of treatment effect and that a viral load value <50copies/ml is biologically meaningful. Whilst it is possible that at the low levels of viral [replication] evolution is occurring in individuals with detectable virus above three copies/ml but below 50 copies/ml, it does not seem to impact the treatment effect over the course of four years of follow-up.

Adherence

Several studies looked at the way in which adherence may be improved by manipulating characteristics of the treatment regimens. A survey of 504 HIV positive individuals across France, Germany, Italy, Spain and the United Kingdom reported a high level of interest in once a day regimens with patients anticipating that they would adhere to medication more successfully.

The small number of individuals in the survey who were on once daily regimens described fewer missed doses.

Perhaps the most interesting element of the survey was the preference for dosing schedules according to tablet volume. Individuals offered eight or more pills per day in two-thirds of cases preferred to divide the medication into twice a day dosing. As the number of pills in the regimen declined, an increasing preference for taking all of the medication at once increased, such that regimens involving six pills would be preferred once a day by 59 percent of individuals, for regimens containing four pills, 84% preferred once daily and regimens containing three pills, 92% of individuals wanted once daily dosing.

This suggests that if once a day dosing of antiretroviral medication is to become a common reality, consideration to making the regimen maximally compact remain important.

One way of doing this is to make combination tablets. The available combination tablets all involved pairs or triplets of agents all owned by a single company. A company from India presented bioequivalence data indicating that a fixed dose tablet of d4T, 3TC and nevirapine can be readily and cheaply made.

This combination tablet produced by Cipla Pharmaceuticals, is now providing triple antiretroviral therapy in some parts of the developing world at a price of one US dollar per day. The problem with such a tablet is that it breaches the patents and intellectual property held by the pharmaceutical companies that develop these products.

This may potentially act as a disincentive for pharmaceutical companies to develop new antiretroviral agents for fear that their return on investment or even the recuperation of their original investment may be impacted by companies that ignore patents. It therefore behoves the pharmaceutical companies to cooperate with each other to produce a wider range of combination tablets for availability in both the developing and the developed worlds.

A retrospective comparison of prescription refills in individuals receiving Combivir tablets compared with individuals receiving separate dosing with AZT and 3TC reported that adherence was substantially better and fewer therapy days missed in individuals who took the combination tablets relative to the separate dosing.

Other factors identified in the study by multivariate logistic regression that were associated with better adherence included male sex, having fewer than three antiretroviral pills per day, receiving a non-nucleoside reverse transcriptase as an additional agent and having received therapy for less than 12 months.

In subgroup analyses, evidence that adherence to physician visits, absence of active psychiatric illness, alcohol or illicit drug use, and the presence of HIV symptoms were all important to adherence, and these profiles benefited from the use of the combination tablets.

Identification of individuals who may be at risk of poor adherence and management of factors which contribute to poor adherence prior to the initiation of therapy are likely to be important in managing treatment success.

In addition, this study underlines the value of combination tablets in easing the burden of therapy and reinforces the observation from studies in other areas of medicine that adherence declines with time and therefore should be something that is raised at every clinic visit rather than simply around the time of therapy initiation.

Once daily regimens

Data on several once a day regimens or potential once a day drugs were reported at the conference. The pro-drug of amprenavir, Fos-amprenavir (aka GSK 908) given as two pills once a day in combination with two pills of ritonavir showed similar responses to twice daily nelfinavir in antiretroviral naive individuals initiating therapy with a backbone of abacavir plus 3TC.

The Fos-amprenavir group reported a trend to better anti-viral effects in individuals who commenced therapy with very high viral loads (> 500,000 copies/ml). The tolerability of this agent appeared somewhat better than nelfinavir with a significantly lower rate of diarrhoea. However, somewhat greater elevation in fasting triglycerides was seen in the Fos-amprenavir group.

The two pills once a day protease inhibitor atazanavir was also discussed. Patients completing a randomised comparative study of atazanavir versus nelfinavir in first-line therapy (in which atazanavir was superior to nelfinavir at the cut-off of 400 copies/ml but not for the 50 copy assay) were switched from nelfinavir to atazanavir. Patients in this ‘roll-over’ study reported maintenance of virological control after switching and significant declines in total cholesterol (by 16%), LDL (by 21%) and triglycerides (by 28%) (p< 0.0001) as well as a significant increase in protective HDL (by 5%, p< 0.05). These data are in keeping with other prospective data that indicate that atazanavir is metabolically benign.

A review of safety information with the extended release formulation of stavudine (Zerit), which has recently been approved in the US, was also reported. The two main licensing studies for this agent (known as studies 096 and 099) both evaluated the efficacy of d4T XR with the current formulation of d4T in treatment naïve patients who also received 3TC and efavirenz. Across the studies 466 individuals received d4T XR and 467 individuals received the currently in use immediate release (IR) formulation.

No differences in adverse event rates of any grade or any relationship to treatment were observed. Discontinuations due to any adverse events were reported in 5% of d4T XR and 7% of d4T IR patients. Peripheral neurological symptoms thought related to study treatment were reported in 3% of d4T XR and 6% of d4T IR recipients, discontinuations due to neuropathy symptoms occurring in <1% of XR and 2% of IR patients.

Lipodystrophy, as assessed by investigators, was reported in 3% of XR and 5% of IR patients, with <1% of XR and approximately 2% of IR patients being specifically described as having lipoatrophy. Symptomatic hyperlactataemia or lactic acidosis occurred in three patients in the XR group and six patients in the IR group. Importantly, of the nine individuals who developed symptomatic hyperlactatemia or acidosis, most had known risk factors for this problem.

Of the nine individuals on d4T XR or IR who developed lactate problems, seven were female, three obese (BMI > 30) and four overweight (BMI 25 to 30). Taken together, these data suggest that the new formulation of d4T may have a somewhat lower risk of drug toxicities which have been suggested to be related to mitochondrial inhibition. More prospective data are needed to confirm this view. With regards to other adverse events within the studies, no differences were observed for shifts in haemoglobin, hepatic transaminase, lipase, or elevation of triglycerides.

Lipid profiles on therapy with protease inhibitors

The DAD study is a prospective study incorporating multiple HIV treatment databases and among more than 12,000 individuals includes 7,729 individuals currently receiving protease inhibitors. The most commonly used protease inhibitor regimens in the cohort are nelfinavir (Viracept) (2,574 individuals), indinavir (2,354 patients), and ritonavir-based double PI regimens (1,464 patients). The median cumulative exposure to protease inhibitors in the cohort is 30 months.

The study is evaluating cardiovascular risk factors and the possible impact of antiretroviral agents on cardiovascular disease. Of note, 44 percent of the patients in the cohort are current smokers and only 5% of patients are currently treated with either antiplatelet or lipid-lowering therapy.

Data presented at this meeting looked at differences at entry to the cohort between protease inhibitors with regards to dyslipidaemia. Dyslipidaemia was defined for total cholesterol, HDL, total cholesterol to HDL ratio and triglycerides by the cut-offs used in the USA national cholesterol education programme (NCEP).

The proportion of patients with a total cholesterol in the intervention range (greater than or = 6.2 mmol/litre) was highest in individuals receiving ritonavir or a ritonavir-based PI regimen (37.2% of individuals) and least in individuals receiving saquinavir (16%).

Rates of cholesterol elevation with indinavir (Crixivan), amprenavir (Agenerase) and nelfinavir (Viracept) were similar (23% to 25%). The proportion of patients with low HDL (< 0.9 mmol/litre) was highest amongst amprenavir-treated patients (41.9%) and least amongst nelfinavir recipients (20.4%).

The proportion of individuals with low HDL were similar amongst indinavir, Fortovase (saquinavir), ritonavir, and regimens containing two PI’s (29 to 33%). With regards to the ratio of total cholesterol to HDL, elevated ratios (> or = 6.5) were observed most commonly in ritonavir-containing regimens (30.5 to 31.4%) and least common in saquinavir- (14%) and nelfinavir- (16%) treated patients with indinavir and amprenavir lying intermediate to those extremes (23.4% and 25.8% respectively).

With regards to triglycerides elevation (> or = 2.3 mmol/litre) saquinavir again proved the most benign of the agents (28.5% of individuals having elevated values) and ritonavir the most problematic (61.8%). Of note, patients receiving amprenavir, a protease inhibitor often considered to have a “better than average lipid profile”, triglycerides elevation was observed in 51.6% of patients, whereas elevation was only seen in 34.1% of indinavir recipients and 33.5% of nelfinavir recipients.

These data are consistent with previous smaller cohort studies that support the idea that saquinavir is the approved PI least likely to be associated with lipid elevation and regimens which include ritonavir have a greater chance of being associated with dyslipidaemia.

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