Yasmin Halima and Rob Camp attended the one-day Pharmacology Workshop held immediately after CROI in February 2004. Here is their report on some kooky, if not explosive, combinations. Thanks to all the presenters for reviewing their data.

Statins + HAART
Many HIV+ people are currently treated with statins to manage lipid elevations. Understanding the pharmacologic interactions between statins and HIV drugs is essential. Some statins have been implicated more than others in their potential for interactions with antiretroviral therapies.

Implementing lifestyle modifications like smoking cessation is extremely important. Dieting is also an efficient way to lower cholesterol levels and can lead to reductions of up to 10%. To reduce cholesterol levels even more significantly, the use of a statin to lower the LDL-C levels may be needed.

Hydrochlorothiazide(a diuretic and antihypertensive drug, trade name Hydrodiuril) and atorvastatin should control blood pressure and LDL cholesterol. But, myalgias and mild diffuse muscle weakness are not uncommon after a short time. Serum LFTs and CPK stats should be done to see if either is elevated; the statin could be responsible for muscle toxicity. Stopping statins in this case would be recommended. Switching to fenofibrate can reduce VLDL but is not as effective in reducing LDL-C elevations.

• Statins are not the same either in terms of efficacy or drug-drug interactions
• All statins have the capacity for severe toxicity that include rhabdomyolysis and hepatic dysfunction, which is dose- (concentration-) dependent
• Understanding the metabolism of statins will make predictions of drug-drug interactions possible

Structure of statins
Simvastatin and lovastatin are lactone pro-drugs that have to be converted into a hydroxy-acid form to be more lipophilic and active. Rosuvastatin (Crestor) is the newest in the class. Statins are metabolised by CYP450 into both active and inactive metabolites.

Relative potency and metabolism of statins

Statins can reduce LDL-C by as much as 50%. Table shows approximate levels needed to reduce LDL-C by 30%.

Impact of CYP450 inducers on statin metabolism
Simvastatin is metabolised to simvastatin-acid, although a significant portion of it is metabolised by the CYP3A isoform. The inhibition of CYP3A4 can lead to fairly significant increases in simvastatin-acid levels and toxicities. A study investigating the impact of RTV on the metabolism of statins showed remarkably high accumulation of simvastatin-acid levels, with increases of ∼3000%.

Pravastatin is metabolised differently and involves multiple oxidation pathways through the CYP450 system, but not CYP3A, so it is actually reduced by some 50% when coadministered with RTV.

Atorvastatin has two main active metabolites generated by CYP3A, and inhibition of CYP3A4 will again lead to increases in atorvastatin; the difference is that it actually has a decrease in the levels of the active metabolite, so the increase in total active atorvastatin activity is not that large (< 2-fold increase with RTV).

With NFV, similar results are seen—atorvastatin levels increased and simvastatin levels increased significantly. Data with lopinavir/r (Kaletra®) also shows increases in atorvastatin by up to 5-fold, although in this study only the unchanged atorvastatin levels were examined and not the total active levels of atorvastatin. Kaletra did not show any significant changes with pravastatin.

Other studies have shown that pravastatin exposure is reduced by 50% with use of RTV and SQV, by 40% with EFV and by 50% with NFV. EFV has been shown to be a potent inducer of simvastatin metabolism leading to reductions in exposure of 60% and of atorvastatin by 30%. Significant reductions in simvastatin, atorvastatin and pravastatin levels result in a slowing down of the LDL-C reduction in the presence of EFV.

A simple analysis of the data available on statins would suggest that pravastatin and fluvastatin are safe to use with CYP450 3A4 inhibitors, although there could be more data on fluvastaitin, and the efficacy of pravastatin may be "compromised" (its metabolism is induced). Atorvastatin should be used with caution, as it could get dangerously high with PIs and uselessly low with EFV. Simvastatin and lovastatin should not be co-administered (they interact severely with CYP3A4 inhibitors (all PIs, although not EFV).

Rosuvastatin data is unknown right now and should be avoided right now with HAART. There are concerns about rhabdomyolysis. The package insert states that cyclosporine increases rosuvastatin levels by 12-fold. Direct interactions studies are currently underway.

There are currently no interaction data between statins and NVP, but until there are, the effects should be suspected to be similar to EFV.

Smoking cessation drugs and their interactions with HIV therapies have not been looked at definitively, but there may be an induction effect.

Bupropion (probably metabolised through CYP2B6) is contraindicated with RTV (probably an inducer, not an inhibitor, of CYP2B6) and the use of 150mg QD may achieve therapeutic levels with patients on boosted PIs.

Tenofovir and other NRTIs
An important factor for all nucleoside and nucleotide reverse transcriptase inhibitors is that they need to be phosphorylated intracellularly into the DP (diphosphate) and TP (triphosphate) forms.

Tenofovir (TDF) has a complex metabolic process leading to the possibility of inter-patient variability and response.

TDF has been shown to increase the plasma concentrations of ddI although the mechanism of this interaction is as yet unclear. The active forms of nucleosides like ddI and nucleotides such as TDF are phosphorylated derivatives produced inside the host cell. These "anabolites" remain inside the cell and are de-phosphorylated there. The rate of de-phosphorylation may be different from the rate of disappearance (half-life or t_1/2) of the nucleoside in plasma.

Depending on weight, ddI should be dosed at 250mg or 200mg with full-dose (300mg) TDF. The ddI taken 2 hours before the TDF produces approximately the same peak plasma concentration (Cmax) and area-under-the-curve (AUC) of ddI seen in the absence of TDF.

The tenofovir t_1/2 is approximately 17 hours, while its DP half-life can be as long as 50 hours, which explains why TDF is administered as a single daily dose that achieves adequate drug levels to maintain intracellular levels and viral suppression. Intracellular phosphorylation (of either TDF or ddI) is difficult to measure. If DP is the important measure, might we be overdosing at QD? Has this been looked at?

With a serum creatinine of 3.2 mg/dL, which equals a creatinine clearance of approximately 30 mL/min, the TDF package insert recommends 300mg dosed every other day, allowing for sufficient serum concentration levels over the dosing period.

Prolonged treatment with TDF is contraindicated in patients with pre-existing renal insufficiency. Toxicities due to too high concentration levels may result. The dose recommended in the package insert is based on a model of single dose HIV-subjects and as such, HIV+ people need to be cautious. Dosing on alternate days may not be an easy adherence scheme, although treatment on Monday, Wednesday and Friday with the weekend off might work. Drug levels of TDF (according to the chart below), may be sufficient to allow dosing in this way.

In patients with normal renal function, 20% of TDF is excreted renally.

Dosage adjustment for tenofovir for people with altered creatinine clearance

Drug Dosing and Renal Function

Could an increased level of nausea and GI side-effects be related to drug levels when LPV/r is used with TDF? There is some data showing this combination as having an impact on renal function, as well as renal failure in a few patients.

Nelfinavir TDM during pregnancy
The use of antiretroviral drugs in pregnancy is complicated by factors like hormonal and metabolic changes as well as the need for maternal and fetal safety. Use of therapeutic drug monitoring (TDM) can provide guidance for clinicians in the management of patients who have either suboptimal or toxic (super-optimal?) drug levels.

Example: a pregnant woman initially showed a good response to HAART despite low nelfinavir plasma levels, but one fine day her viral load shot up above detectable. The levels of NFV are probably relevant—so the frequency of VL monitoring should be increased. Increasing the dose might help to increase the blood levels of NFV. Doing both (repeating the VL and increasing the dose) would be most appropriate.

Nelfinavir plasma levels may be low during pregnancy. It is unknown whether these low levels are associated with suboptimal antiviral response. With NLF, a TID regimen would maybe give better drug levels, although one retrospective ACTG study said no. Would prospective PK studies on the use of nelfinavir in pregnant women be helpful?

Berger would recommend increasing the frequency of VL monitoring and perform TDM as soon as possible. At 2 weeks after starting treatment, TDM should be undertaken and the interpretation of that result plus the virologic response should be used to adjust the treatment and drug levels.

Resistance and PK
The care of patients with prior experience of multiple antiretroviral agents and a limited number of options for switching presents challenges. The understanding of significant mutations that confer drug resistance and the impact of cumulative changes in the viral mutations can help guide therapeutic choices.

In the presence of many NAMs (nucleoside analogue mutations) plus the M184V, it is unlikely that any NRTI change will have much effect. With 4 or more TAMs (thymidine analogue mutations), there is little impact of new NRTIs, based on both expert opinion and the recent GSK 30009 debacle (TDF + ABC + 3TC is a nix).

The co-administration of TDF and ddI shows an increase in plasma ddI concentrations, and TDF + LPV/r increases TDF levels (see above).

The ability of PIs to inhibit viruses with accumulating resistance mutations is a relative phenomenon. Viruses may not be fully susceptible but may still retain some activity. We need to understand the impact of resistance and to combine what may be partially active drugs in a regimen that confers the greatest cumulative activity. By integrating pharmacologic and virologic interventions we can enhance PI activity and improve therapeutic outcomes.

Pharmacologic principles are based on risk-benefit ratios. ACTG study addresses the question of whether increasing LPV or /r levels has an impact on viral suppression. Balancing the potency of the regimen needs to looked at with any increase in toxicity—will patient adherence be compromised? A small pilot study compared adding 200mg /r + 3 Kaletra tabs to 4 tablets of Kaletra#151;and showed greater toxicity in the extra /r arm both on GI-related toxicities and lipid elevations.

In another recent study involving patients with multiple accumulations of resistance mutations in whom the dosing regimen was increased to 4 Kaletra pills (533mg LPV and 133mg /r), there was an improved response in reaching target concentrations of 5,500ng/ml, which is predictive of a longer-term anti-viral response.

There have been fairly definitive studies that have seen the non-favorable interaction of LPV/r + APV (or 908) to where blood levels of both drugs are lowered to a dangerously ineffective level. This scenario is complicated with many variables. Significant interactions are likely between APV and LPV/r, with reductions in levels of LPV and APV of up to 50%. Although avoiding this combo is the most straightforward strategy, TDM might be worthwhile to guide the dosing strategy, in the case of there not being another choice. 908/r (vs APV/r) has further complicated this issue and we have little data on the possible interactions between 908/r and LPV/r. Although these two drugs are not exactly bioequivalent, they are chemically close enough to each other to raise the warning flag—interactions-wise, there has been little difference between the two.

We should also be mindful of the fact that much of the 908 data is based on un-boosted levels, which is probably not a real-life scenario.

Given the complex interactions, if this combination must be used, TDM is probably a good idea to correct for any imbalances of the already adjusted dosing. TDM should provide an effective therapeutic range, although the side effects are not known and could very well be severe.

C Flexner, Johns Hopkins University, USA, T Gulick, Cornell, USA and J Schapiro, Stanford University, USA, T Blaschke, Stanford University, C Boucher, University of Utrecht, The Netherlands, D Burger, University of Nijmegen Medical Center, The Netherlands, C Fletcher, University of Colorado, USA, J Gerber, University of Colorado, Denver, USA, 11TH Conference on Retroviruses and Opportunistic Infections, Post-Conference Workshop, 12 Feb 2004, San Francisco, USA. Wit et al, 2nd IAS Conference, Paris, abstract 129. Fichtenbaum et al, AIDS 2002, 16:569-77, Hsyu et al, AAC 2001, 45:3445-50, Carr et al, abstract 1644, 40th ICAAC, 2000, Gerber et al., 2nd IAS, abstract 870, 2003, Gerber et al, CROI 2004, abstract 603

[excerpts]

It is more and more difficult to imagine anti-HIV treatments as life-long prescriptions, given the side effects described in the long term, such as lipodystrophy (found here in nearly 60% of patients), metabolic disturbances, a possibly increased cardiovascular risk, mitochondrial toxicity and altered quality of life. In other words, the inconvenience of a very long-term treatment may outweigh the benefit of maintaining the CD4 cell count at a high level, considering that treatment beyond 2 to 4 years will not result in a significant further reduction of the HIV-1 DNA load. For patients with high CD4 cell values (e.g., >400 cells/mL) after this time [>2-4 years] on HAART, would it be reasonable to consider stopping therapy when the level of HIV-1 DNA reaches its lowest plateau and then wait for the patients to meet again the criteria for treatment initiation?

The present study, although limited in its conclusions by the small number of patients, stresses the leveling off, with time, of the effects of HAART. Maintenance of therapy beyond 3 years is necessary to avoid the replenishment of the compartment of cells actively producing virus, but any additional benefit in terms of reduction of the viral reservoir seems highly unlikely.

[ Among patients enrolled in this study ] there was only a very slight gain in CD4 cells after 18 months of treatment. Interestingly, the absolute increase in the CD4 cell count was not different in the patients with CD4 baseline values below or above the median value of the population, and there was no marked further benefit in the long term in either group. The majority of patients had reached a CD4 cell count constantly >400 cells/mL by month 30, and nearly all of those with a baseline CD4 cell count above the median (135 cells/mL) had attained that level at the end of follow-up. For patients who have reached this level of CD4 cell counts, a reasonably safe level both for the protection against opportunistic infections and for considering treatment interruption, the immunological benefit of maintaining HAART appears debatable.

In summary, the data presented here show that HIV-1 DNA does not seem influenced by HAART after the third year and confirm that the CD4 cell count gain is less apparent after 18 months on treatment. Based on these observations, we question the benefits of a lifelong treatment for HIV infection.

Source: Jean-Pierre Viard and colleagues: "Effect of highly active antiretroviral therapy over 5 years." AIDS 2004;18:45-49.

Building on the success of the First International TB/HIV Community Education and Mobilization Workshop, held in conjunction with the 33rd International Union Against Tuberculosis and Lung Disease (IUATLD) Conference on Lung Health in Montréal in 2003, the Second International TB/HIV Community Education & Mobilization Workshop had the following objectives:

1. To educate HIV community representatives on the various aspects of TB/HIV coinfection research, prevention, treatment, and policy.
2. To empower HIV community representatives to mobilize and disseminate information about TB/HIV coinfection to their local communities.
3. To give HIV community representatives the skills necessary to help their communities understand, participate in, and provide community input in research and clinical trials.
4. To provide an opportunity for international HIV community representatives to develop working relationships work with WHO, the Stop TB Partnership, the Global Fund, and other stakeholders to more effectively represent affected communities in prevention, research, treatment, and care programs focusing on TB/HIV coinfection.
5. To provide an opportunity for international HIV community representatives to develop working relationships with national and regional public health and TB and HIV/AIDS program officials so that they may work together to implement future TB/HIV initiatives.
6. To provide an opportunity for international HIV community representatives to develop plans and strategies to mobilize communities, policymakers, and resources to better fight TB/HIV at the country and regional levels, and participate in global policy dialogue.

The 2nd workshop incorporated several changes made to address the needs identified by participants in the 1st workshop. Fifty participants took part. The workshop was two-and-a-half days long. There were more opportunities for small group interactions, and longer strategy sessions. As in 2002, participants at the 2nd workshop attended IUATLD conference sessions on TB and TB/HIV coinfection, met with TB program officials, and networked extensively at the Union meeting to develop stronger relationships with national and regional public health, TB and HIV/AIDS program officers, the World Health Organization (WHO), the Stop TB Partnership, the Global Fund to Fight AIDS, TB and Malaria (GFATM), and others to more effectively represent affected communities.

Over one million people worldwide die annually of tuberculosis, according to the World Health Organization. TB, a 100 percent curable disease, is today silently causing more deaths than ever in the history of mankind.

The case for a closer look at the world's TB epidemic could not have been made more forcefully, as scientists and advocates met for four days in the fall all of 2003 to examine current trends, scientific advances and progress made in controlling the global epidemic.

The scientists met under the aegis of the IUATLD. As researchers exchanged data during the conference, treatment advocates attended a TB/HIV co-infection education and community mobilization workshop convened by the Treatment Action Group (TAG). The workshop was designed to stimulate discussions about the key issues fueling TB/HIV co-epidemics and strategies for addressing them.

For the many of the over 60 treatment activists from 31 countries who attended the workshop, discussions in the various groups were an eye-opener to the untold havoc TB is wrecking in many communities, its intrinsic linkage with HIV and the need to adopt proactive strategies to stem this 'silent epidemic.'

Various factors were identified as fueling this, such as the rising incidence of new HIV infections, poor diagnostic facilities, low case detection of new TB infections and lack of trained health care professionals. Other factors include "brain drain," under funding of national TB programs, lack of political leadership, insufficient drug supply at TB treatment centers and the incidence of multi-drug resistance.

Situation reports presented on the state of TB programs in many countries including Niger, Ukraine, South Africa, Brazil, Zambia, Thailand, Kenya, and Nigeria revealed that, despite over three decades of existence, national TB programs still remain grossly under-funded, and require stronger political commitment in stemming the tide of the epidemic.

It seemed TB programs have next to nothing, compared to national HIV programs which enjoy huge funding budgets, external donor support, high political will and commitment, civil society and community involvement, established peer support groups, and trained human resources.

Dr. Gani Alabi, a WHO staffperson who works on TB in south-western Nigeria, said, "Nigeria has a strong HIV/AIDS committee headed by the President, a multi-sector committee comprised of representatives from many sectors, including numerous civil society groups working on HIV/AIDS. These interventions receive a lot of funding and are well staffed; unfortunately, TB control programs in the country lack this type of support."

He continued, "Although a free TB treatment policy exists, many of the TB treatment centers do not have drugs for their clients when they need them. WHO plans to start the integration of TB/HIV programs in six selected states in the country, but political will and financial commitment is needed in order to make this a reality."

Karyn Kaplan of the Thai AIDS Treatment Action Group (TTAG) also pointed out that while the Global Fund to Fight HIV/AIDS Tuberculosis and Malaria presents a great opportunity to fund proposals for expanding TB interventions, there has been little or no meaningful engagement of PLWHA or those affected by TB in the Country Coordinating Mechanisms in countries which ought to push for requests for funding.

At the end of in-depth deliberations, participants recommended the integration of existing HIV and TB programs, and the need to mobilize community support for the Directly Observed Treatment Strategy (DOTS) in reducing the spread of TB.

Activists also proposed various other follow up activities at country levels to support DOTS. High on the list of recommendations was the need to organize treatment literacy workshops and community education on the signs and symptoms of TB, adherence and drug compliance. They also agreed to strengthen national coalitions on TB and mobilize for greater political and financial commitment from governments, donor agencies and civil society groups for TB control programs.

How can AIDS activism contribute to TB control?
AIDS activist movements have developed skills and strategies that can be adapted for use in campaigns against TB and TB/HIV. One of the first key strategies is to increase national spending on research, prevention, treatment and care. Increased funding for the National Institutes of Health has been one of TAG's key goals.

The budget for TB research is quite small compared with the disease burden. While the NIH spends $2.7 billion each year on HIV/AIDS research, it spends just over $200 million on TB research. More research is needed on shorter TB regimens, better drugs, point-of-use diagnostics, antiretroviral and TB drug-drug interactions. Drugs to prevent and treat opportunistic infections, such as cotrimoxazole and isoniazid, are also critical components of TB/HIV care.

There have been different phases of TB advocacy over the past 100 years, from the sanitarium movements to DOTS. There is now a push to link to the strengths of the international AIDS treatment access movement to TB advocacy, but the core strategy of PWA's involvement at all levels is difficult to replicate with TB, which unlike HIV is not a life-long condition.

In the U.S., the $10,000/year price of AZT upon its approval in 1987 created outrage which contributed to the founding of ACT UP. "Insider/outsider" strategies can be useful and complementary: activists identify problems and meet with government policy makers at the same time as they generate pressure via media and social mobilization.

Drug pricing remains an issue, although continued pressure has brought down the price for generic antiretroviral therapy. In less developed countries, however, antiretroviral therapies will need to be free in most settings. Wealthy countries will need to provide the resources to make this happen. Even if antiretroviral therapy programs ultimately cost $500 per person year for three million people, that is only $1.5 billion—which is the weekly cost of the U.S. occupation of Iraq. ¤