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After Toronto, 46th ICAAC Offers Back to Basics

By Keith Alcorn, Edwin J. Bernard, Michael Carter, Adam Legge, Mark Mascolini and Derek Thaczuk

October 2006


After Toronto, 46th ICAAC Offers Back to Basics
After the marathon-like challenge presented by the 16th International AIDS Conference held in Toronto a month prior -- a challenge that tested the stamina of even the youngest and fittest of conference-goers -- the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 27-30, 2006, in San Francisco, was a welcome relief in its staid and singular focus on the presentation of data offering insights into the challenges a variety of patients and their physicians are facing in the second decade of highly active antiretroviral therapy (HAART), as well as reviews of how to make optimal use of antiretroviral regimens constructed from within the existing HAART armamentarium. The big news at this year's ICAAC, however, was on the antiretroviral pipeline, with previews of how a new generation of drugs may help make the difference between life and death for countless millions of men, women, and children living with HIV/AIDS.


On "Naive-te," Older Age, and Discordance

16% of ART-Naive Entering GSK US Studies Resistant

Sixteen percent of antiretroviral therapy (ART)-naive patients enrolling in GlaxoSmithKline-sponsored clinical trials in the United States last year already had resistance to at least one antiretroviral drug, according to data presented by company researchers.1 Furthermore, the frequency of resistance has almost tripled since 2000, and almost two-thirds of those with resistance in 2005 showed resistance to a nonnucleoside reverse transcriptase inhibitor (NNRTI), the backbone of first-line antiretroviral regimens for the majority of HIV-positive patients initiated on ART in the United States.

The study analyzed data from 2,035 ART-naive patients who enrolled in GSK-sponsored studies in the United States between 2000 and 2005. The recruited population was predominantly male (84%), 48% were white and 36% African American, with a median CD4 count of 252 cells/mm3. There was a slight disparity in recruitment by year (less than 250 people were recruited to studies in 2000 and in 2005, but over 400 individuals entered studies in each of the other years). Exposure category data were available on 1,529 patients: 67% were gay men, 35% heterosexual, 5% had acquired HIV through injecting drug use, and 2% through blood transfusion.

The researchers used two different classification systems for resistance to analyze the prevalence of resistance: the International AIDS Society-USA (IAS-USA) definitions2 and the Stanford University HIV Drug Resistance Database definitions.3

NNRTI resistance prevalence grew from 2% in 2000 to between 10% and 11% in 2005, while nucleoside reverse transcriptase inhibitor (NRTI) resistance prevalence grew from 4% to 5% in 2000 to 7% to 8% in 2005, depending upon which classification system was used. However, the two systems were in close agreement for all years and all drug categories regarding resistance prevalence. Protease inhibitor (PI) resistance showed less of a trend toward increase, and remained below 5% throughout the period.

In the multivariate analysis, the likelihood of participants having any resistance mutations significantly increased over time between 2000 and 2005, (P=0.0151 IAS-USA definitions or P=0.0219 Stanford University definitions, respectively). Similarly the likelihood of having either NRTI or NNRTI mutations significantly increased over time by either IAS definition (P=0.0419, P=0.0109, respectively) or Stanford University definitions (P=0.0116, P=0.0074, respectively).

When looking at specific demographics of study participants, multivariate analysis showed no significant difference between gay men and heterosexuals in the risk of resistance (although by using the Stanford University definitions, heterosexuals appeared to have a lower risk of acquiring PI resistance). The analysis also revealed a significantly lower risk of resistance overall among African-American men and women compared to whites (approximately 40% reduced risk), and a lower risk of NRTI (53% lower risk). The Stanford University and IAS-USA databases did not agree on whether a reduced risk of resistance for NNRTIs and PIs also applied to African Americans. In addition, a greater risk of resistance in later years among people with lower viral load (

ART Suppresses Viral Load in Older Patients, but CD4 Cell Recovery Impaired

Individuals who are diagnosed with HIV aged 50 years and above have as good a response to ART as patients who are aged under 40 when they receive their HIV diagnosis.4 However, researchers from [affiliation] found that even though older patients do well on ART, they are nevertheless more likely to progress to AIDS and die than do younger patients. In another study also looking at older patients, Spanish researchers found that although older age did not reduce the odds of a patient achieving and sustaining viral suppression with anti-HIV therapy, but it yield lower increases in CD4 count for patients on ART as they aged.5

In the California study, researchers wished to gain a better understanding of the characteristics of HIV infection in older patients. For the purpose of the study, they defined "older" as 50 years of age or above at the time of HIV diagnosis. Over a six-year period (1998 to 2004), data were gathered on all new HIV diagnoses at 11 hospitals in California. Patients were divided into two groups on the basis of their age: the first group consisted of just under 500 patients who were aged 50 years or older at the time of their HIV diagnosis; the second group was composed of almost 4,000 patients aged between 18 and 40 years at the time of HIV diagnosis. Information was gathered for both groups of patients and compared regarding risk factors for HIV infection; baseline viral load and CD4 count; response to ART; progression to AIDS; and death.

Some significant differences existed between older and younger patients at the time of their HIV diagnosis (Table 1). Older patients were more likely to be male (84% versus 75%, younger patients, P

Table 1. Traits of Older, Younger Individuals at HIV Diagnosis

Table 1. Traits of Older, Younger Individuals at HIV Diagnosis


At the time of their HIV diagnosis, older patients had a median CD4 count of 229 cells/mm3 compared to a median count of 360 cells/mm3 in younger patients. This difference was statistically different (PThe researchers next compared how older and younger patients responded to ART. Both groups of patients had comparable viral load before treatment was initiated, but after six months of treatment significantly more older patients had a viral load below 500 copies/mL than did younger patients (85% versus 66%, PDespite having better virologic control of HIV, CD4 counts were lower among older patients than younger patients six and 12 months after starting ART by approximately 100 cells/mm3 (313 cells/mm3 versus 415 cells/mm3; 350 cells/mm3 versus 449 cells/mm3). This difference was maintained five years after treatment was initiated (483 cells/mm3 versus 547 cells/mm3). No tests for statistical significance were provided by the researchers, but at all time points measured after the initiation of ART, both younger and older patients had median CD4 counts high enough to suggest adequate protection against AIDS-defining illnesses.

Finally, the researchers compared outcome in their patients. They noted that older patients were significantly more likely to progress to AIDS (P3.

The Spanish study produced broadly similar findings. It included 187 patients who had a CD4 count below 200 cells/mm3 and were ART-naive when treatment was initiated. Although age had no effect on the likelihood of achieving and maintaining viral load for up to 18 months after starting antiretroviral drugs, each additional 10 years in age significantly reduced (by 90%) a patient's odds of achieving a CD4 count of 350 cells/mm3 after 18 months of ART (P=0.02).


Immunologically Discordant ART Response, Increased Disease Progression Risk

HIV-positive patients whose ART succeeds in suppressing viral load to undetectable levels, but who nevertheless fail to experience an increase in their CD4 count above 200 cells/mm3, remain at a high risk of experiencing progression to AIDS and death in the first year of treatment.6

The objective of ART is to suppress the replication of HIV in the blood to undetectable levels (below 50 copies/mL), thus allowing the immune system to strengthen and preventing the emergence of AIDS-defining infections and tumours. However some patients who commence ART experience an immunologically discordant response to their treatment. This means that although their viral load is suppressed to undetectable levels, their CD4 count fails to increase to above 200 cells/mm3.

Canadian researchers wished to determine if a failure to achieve a CD4 count above 200 cells/mm3, despite having an undetectable viral load, was associated with an increased risk of progression to AIDS and death. They therefore conducted a study involving 299 patients who started ART between 1996 and 2003.

To be included in the study, patients needed to have had two consecutive viral loads below 50 copies/mL. The researchers then divided patients into two groups according to their CD4 count response to ART: patients whose CD4 count had increased to at least the target level of 200 cells/mm3, and those whose CD4 count had not. Rates of progression to AIDS and death were then compared between the two groups during the first year of ART. The median age of the study population at baseline was 42 years, 86% were male, 15% were (or had been) injecting drug users, 27% had been diagnosed with AIDS, and median CD4 count was 80 cells/mm3.

A total of 97 patients (32%) failed to experience an increase in their CD4 count during the first year of ART, despite having effective control of HIV. There were 21 new AIDS-defining events, and six deaths. When the researchers looked at the factors associated with an increased risk of HIV disease progression, they found that patients whose CD4 counts did not increase to at least 200 cells/mm3 a year after commencing virologically effective ART had a hazard ratio of progression to AIDS or death of 3.94 compared to patients whose CD4 count increased to above 200 cells/mm3.


HCV Infection Limits ART-Associated Cholesterol Increases

HIV-positive patients on ART who are also HCV-coinfected are less likely to have abnormally high levels of cholesterol or triglycerides.7 Hyperlipidemia is a recognised complication of ART, but exactly how HIV, HCV, hepatitis B virus (HBV), and lipids interact is not fully understood.

Canadian researchers studied 729 HIV-monoinfected patients and compared their lipid levels with 305 HIV/HCV-coinfected patients. All were on ART and had their lipid levels checked at the beginning of the study and again at six and 12 months. The differences between the two groups were marked and statistically significant.

For those only infected with HIV the total blood cholesterol levels rose by an average of 0.99 mmol/l at six months and by 1.43 mmol/l at 12 months. But in those with HIV/HCV coinfection cholesterol rose by only 0.16 (PDisorders of the metabolism, such as high cholesterol levels, led 7% of HIV-monoinfected patients to stop or change their ART, compared to less than 1% of those who were HIV/HCV-coinfected. Twenty-two percent of HIV-infected patients went on to take a lipid-lowering drug, such as a statin, compared to just 4% of those with coinfection.

The researchers also looked at what happened when coinfected patients were treated for their HCV infection using interferon (IFN). Intriguingly they found that successful treatment of HCV means that the protection against raised lipid levels with ART is lost. Total cholesterol rose by 0.85 mmol/l in coinfected patients whose HCV levels dropped long-term after treatment with IFN. But the level was unchanged in patients who did not respond to IFN.

The researchers also looked at whether HBV infection had any effect on lipid levels but found nothing to suggest it did.


HAART News 2006

ATV/EFV NRTI-Sparing Regimen Effective, Raises Lipid Levels

Regimens that spare NRTIs and consist of ritonavir (RTV)-boosted atazanavir (ATV) plus efavirenz (EFV) demonstrate potent antiviral activity in treatment-naive patients, but raise levels of triglycerides and both LDL and high-density lipoprotein (HDL) cholesterol.8

Given concerns about long-term side effects such as lipoatrophy and mitochondrial toxicity associated with certain NRTIs, researchers have explored the use of NRTI-sparing regimens that include only NNRTIs and protease inhibitors PIs. However, NRTI-sparing regimens may cause toxicities of their own, in particular elevated lipid levels. In studies to date, ATV has been shown to cause fewer lipid abnormalities than other drugs in the PI class.

Bristol-Myers Squibb researchers presented data on one such regimen. In the multicenter, open-label BMS-121 study, 61 participants initiated on ART for the first time were randomized and began treatment with one of two doses of RTV-boosted ATV (300/100 mg or 400/100 mg once daily) plus 600 mg EFV for 48 weeks. No NRTIs were used.

Most participants were men (85%), nearly half (49%) were white, 43% were African American, and the mean age was 37 years. At study entry, participants had CD4 counts of at least 50 cells/mm3 (median 305 cells/mm3), viral load levels of 1,000 copies/mL or higher (median 4.97 log10 copies/mL), and fasting triglyceride levels below 200 mg/dL (considered the upper limit of normal).

Overall, viral load fell by a mean 3.24 log10 copies/mL by Week 48. In an intention-to-treat analysis (drop-outs counted as failures), 75% of patients in the 300/100 mg ATV arm and 67% in the 400/100 mg ATV arm achieved viral suppression below 400 copies/mL; 63% and 61%, respectively, had viral loads below 50 copies/mL. Mean CD4 counts increased by 271 cells/mm3 in the 300/100 mg group and 250 cells/mm3 in the 400/100 mg arm.

In an observed/as-treated analysis (looking only at patients who successfully completed the study), 92% and 96% in the 300/100 mg and 400/100 mg arms, respectively, reached viral load levels below 400 copies/mL, while 77% and 87% had viral load below 50 copies/mL.

With regard to side effects, moderate to severe (grade 2 to 4) treatment-related adverse events were seen in nearly one-third of participants (26% in the 300/100 mg arm and 30% in the 400/100 mg arm), with the most common being insomnia, skin rash, diarrhea, and dizziness. A total of 12 patients stopped treatment prematurely, but only two discontinuations were due to adverse events.

Grade 3 to 4 bilirubin elevation was observed in 13% of patients in the 300/100 mg arm and 40% in the 400/100 mg arm, though none discontinued for this reason. For grade 3 to 4 liver enzyme elevations, the rates were 10% and 7%, respectively, for alanine aminotransferase (ALT), and 7% and 3% for aspartate aminotransferase (AST).

Looking at lipid changes, fasting triglyceride levels rose by 48% from baseline in the 300/100 mg arm and by 63% in the 400/100 mg arm. These elevations were greater than those observed in most studies of ATV or EFV to date, although none were worse than grade 2.

Total cholesterol increased by 29% and 32% from baseline in the 300/100 mg and 400/100 mg arms, respectively. From a clinical perspective, it is more useful to consider the different types of cholesterol separately. Low-density lipoprotein is a risk factor for cardiovascular disease, while HDL has a protective effect. Low-density lipoprotein increased by 11% in the 300/100 mg arm and by 13% in the 400/100 mg arm, while HDL rose by 54% and 45%, respectively.

None of the total cholesterol or LDL elevations were considered severe (grade 3 to 4), while the HDL increases were greater than those observed in most previous studies of these drugs. Further, the ratios of total cholesterol to HDL and of LDL to HDL (TC:HDL and LDL:HDL) decreased in both dose arms, which is considered to be a more favorable.

The researchers concluded that both dosing regimens of ATV/r plus EFV "were generally safe, well-tolerated and demonstrated potent antiretroviral efficacy through 48 weeks." They added that, "increases in triglycerides, total cholesterol, and LDL cholesterol were observed in both arms and were accompanied by robust increases in HDL cholesterol and decreases in TC:HDL and LDL:HDL ratios." Because both potentially dangerous triglycerides and LDL and protective HDL increased simultaneously, the researchers acknowledged that the long-term implications for cardiovascular health could not be determined.


Trizivir Non-Inferior to Unboosted ATV in Treatment-Naive

After Toronto, 46th ICAAC Offers Back to Basics
Trizivir is non-inferior to unboosted ATV plus Combivir as first-line ART.9 After 48-weeks, 62% of participants on the triple-NRTI regimen achieved viral loads below 400 copies/mL compared with 59% on the unboosted PI, although important differences were seen in patients who initiated ART with viral loads above 100,000 copies/mL, leading researchers to conclude that Trizivir should only be considered as first-line ART in patients with viral loads below this threshold.

Current treatment guidelines from both the United States and the United Kingdom do not recommended a triple-NRTI combination as first-line ART due to Trizivir's reduced potency compared with EFV.10,11 Although unboosted ATV is recommended in the US guidelines as an option for first-line treatment,10 the latest IAS-USA treatment guidelines only recommend the use of RTV-boosted ATV due to concerns over low trough levels of the unboosted drug that might lead to resistance.12 Unboosted ATV is not approved in the Europe for similar reasons, and therefore, UK guidelines do not recommend its use in first-line therapy.11

However, the guidelines do state that there are situations when the triple-NRTI combination of zidovudine (ZDV)/lamivudine (3TC)/abacavir (ABC) could be considered as first-line ART -- notably when NNRTI- or boosted PI-based ART cannot be used, for example when the concomitant treatment of a coinfection, in particular tuberculosis (TB), is warranted since TB treatment can interact with NNRTI- or boosted PI combinations.

The randomized, open-label ACTION study (or ESS100327) effectively compared ABC and unboosted ATV head-to-head, with a common background of ZDV and 3TC in both arms. Participants were randomized to receive one of two triple-drug antiretroviral regimens: ZDV plus 3TC plus ABC (taken as one Trizivir tablet twice daily) or ZDV plus 3TC plus ATV (taken as one Combivir pill twice daily, plus two 200 mg capsules of ATV once daily).

A switch to tenofovir (TDF) was allowed if participants taking ABC experienced a suspected hypersensitivity reaction. Similarly, a switch to unboosted fosamprenavir (FPV) was allowed if participants taking ATV experienced clinical manifestations of hyperbilirubinemia.

Virological failure was defined as viral load reduced less than 1 log from baseline by Week 12, viral load not below 400 copies/mL by Week 24, viral load previously below 50 copies/mL rebounding above 400 copies/mL prior to Week 24, confirmed viral load above 400 copies/mL after Week 24, or unconfirmed viral load above 400 copies/mL at Week 48. None of these definitions meet the current gold standard of a sustained viral load below 50 copies/mL at Week 48, however, which has been used in many recent studies, including those comparing currently recommended first-line antiretroviral regimens: boosted FPV with RTV-boosted LPV and EFV with LPV.

In total, 279 patients were enrolled in the study, 139 were randomized to receive ABC and 140 received LPV. However, one patient in the ABC arm did not receive treatment and this led the researchers to provide a slightly modified intent-to-treat analysis, which they termed, "intent-to-treat exposed (ITT-E)."

Demographic, immunologic, and virologic characteristics were essentially similar in both arms. This was an ethnically varied group, with an average age of around 37 years; one-in-five were women. Baseline viral loads ranged between 5,000 copies/mL and 200,000 copies/mL, and the median baseline viral load was 66,000 copies/mL; median CD4 counts were at least 100 cells/mm3, and the median CD4 count was 268 cells/mm3.

The researchers first presented ITT-E data where switch does not equal failure. They found that overall both arms were similar in efficacy. At 48 weeks, 64% of participants initially randomized to the ABC arm and 63% of participants initially randomized to the ATV arm had sustained viral loads below 400 copies/mL. Both arms had a median CD4 count increase of 147 cells/mm3 from baseline to week 48.

However, there were noticeable differences in efficacy at higher viral loads when the participants were stratified according to baseline viral load above and below 100,000 copies/mL. Only 39% of the 23 participants in the ABC arm with baseline viral loads above 100,000 copies/mL had sustained viral loads below 400 copies/mL at Week 48. In contrast, 64% of the 25 participants in the ATV arm with baseline viral loads above 100,000 copies/mL had sustained viral loads below 400 copies/mL after 48 weeks. However, due to the small number of participants in both arms, this only achieved borderline statistical significance.

During their summation, the researchers also presented more rigorous ITT-E data, in which switch equals failure, and found slightly reduced efficacy at 48 weeks in the study population as a whole: 62% in the ABC arm and 59% in the ATV arm. No CD4 count data were provided for this analysis.

Seventy-five percent, or a total of 103 out of the 138 who began treatment in the ABC arm completed the full 48 weeks, compared with 98 out of the 140 (70%) who began treatment with ATV. The differences were not statistically significant. The most common reason for not completing the study was virological failure. A total of 18 (13%) in the ABC arm and 17 (12%) in the ATV arm met one of the five definitions of virological failure. There were no significant differences between the arms in terms of which of these five definitions they met.

Resistance profiles were somewhat similar between the two arms, with 10 participants in the ABC arm harboring resistant viruses, nine of whom had the M184V mutation (which confers resistance to 3TC and FTC), seven of whom had minor PI mutations. One individual had several thymidine analog mutations (TAMS) and one individual -- strangely, and possibly due to baseline transmitted resistance -- K103N, which confers resistance to NNRTIs. Eleven participants in the ATV arm had resistant virus, nine of whom also had the M184V mutation, six of whom harbored minor PI mutations, and again one had K103N.

Similar numbers in both arms experienced grade 2 to 4 adverse events. Notably 21% and 4% in the ATV arm experienced hyperbilirubinemia and yellowing of the whites of the eyes, respectively. The most commonly reported side effects in the ABC arm were nausea (11% versus 4% in the ATV arm) and fatigue (5% versus 2% in the ATV arm), and 5% had a suspected ABC hypersensitivity reaction.

Lipid profiles were comparable at week 48, with very slight increases of total cholesterol and very slight reductions in LDL in both arms. However, slightly higher increases were noted in triglycerides in participants in the ABC arm (+11% from baseline versus +5% in the ATV arm); and slightly higher increases were seen in HDL in the ATV arm (+21% versus +16% in the ABC arm).

The researchers concluded that although ABC-containing triple-NRTI regimens were non-inferior to ATV-containing PI-based regimens according to the study protocol, Trizivir "remains a viable option" for "select patients naive to therapy" with viral loads below 100,000 copies/mL. However, these data show that neither Trizivir nor unboosted ATV appear to be as potent as the currently recommended or alternative first-line antiretroviral regimens in the most recent treatment guidelines.


NVP Hepatotoxicity After Switch No More Likely at Higher CD4 Counts

Patients with undetectable viral load who switch from current treatment to nevirapine (NVP) when they have a CD4 count above the recommended threshold for starting the NNRTI are no more likely to develop hepatotoxicity than women with CD4 counts below 250 cells/mm3 or men with CD4 counts below 400 cells/mm3.13

Nevirapine has been shown to pose a risk for liver toxicity for treatment-naive patients who are starting their first antiretroviral regimen at relatively high CD4 counts. The degree of risk is different for men and women: men with CD4 counts above 400 cells/mm3 and women with CD4s above 250 cells/mm3 are most at risk for hepatotoxicity. However, the risk has been unclear for those who are already virologically suppressed on a non-NVP-containing regimen, who switch to one that contains NVP, and who have CD4 cell counts above these levels.

Spanish researchers conducted a meta-analysis that pooled the results of four existing studies. To be eligible for inclusion in the meta-analysis, studies had to have switched participants from a successful antiretroviral regimen to one containing NVP while the participant's viral load was still undetectable, and then observed participants for at least three months after switching. The selected studies included a one-year study in patients who switched to NVP from a PI; a randomized study of prednisone as a preventive treatment against NVP-associated rash; a large randomized comparative study of switching from a PI to either NVP, ABC, or EFV; and a study of cetirizine as a preventive treatment against NVP-associated rash).

A total of 410 trial participants were entered into the analysis. Of these, 277 were deemed eligible for the high-CD4 group: females with a CD4 count of 250 cells/mm3 or higher, and men with CD4 count of 400 cells/mm3 or higher. The remaining 133 participants were designated as the low-CD4 group.

Occurrences of liver toxicity (after the treatment switch) were then examined in both groups. The researchers defined hepatotoxicity as happening if: (a) liver enzymes (ALAT or ASAT) increased from normal levels to above 200 units/L, or (b) increased by a factor of three or more if they were abnormally high to begin with.

The study showed a 2% risk of hepatotoxicity in the low-CD4 group, and a 4% risk in the high-CD4 group. However, the statistical difference between the two groups was not significant, and the overall results showed essentially no difference in risk between the low- and high-CD4 groups. The only clear risk factor for hepatoxicity was having elevated liver enzymes at the beginning of the study. There were no deaths, and only a very few patients (1%) developed liver inflammation (hepatitis).

The researchers concluded that their analysis found no evidence of an increased risk of hepatotoxicity for women with CD4 counts above 250 cells/mm3 or men with CD4 counts above 400 cells/mm3 who switch to NVP when they already have undetectable viral load as a result of previous ART.

A second study, conducted at a single treatment center in Munich, Germany, looked at that center's experience of hepatotoxicity in treatment-naive and -experienced patients from 1996 to 2005.14 They defined hepatotoxicity as an ALT five times the upper limit of normal. Their analysis included 507 patients (397 male, 110 female) with a median baseline CD4 count of 219 cells/mm3 in women and 270 cells/mm3 in men. Forty percent of women had a CD4 count over 250 cells/mm3 and 27% of men had a CD4 count over 400 cells/mm3.

The study evaluated 817 patient-years of NVP treatment with a median observation time on NVP of 21 months. At the time of analysis 58% had discontinued NVP treatment, 20% due to treatment failure, 6.7% due to rash, and 7.5% due to liver enzyme elevations. Other reasons for discontinuation were not stated. Of the 38 patients who discontinued due to liver enzyme elevations, 20 of 38 discontinued due to ALT more than five times the upper limit of normal, after a median of 3.6 months on nevirapine. Two patients had acute hepatitis A or B, while the remainder discontinued due to smaller liver enzyme increases.

Among men, 3.9% experienced grade 3 or 4 ALT elevations, compared to 6.3% of women. There was no significant difference by CD4 count in the risk of grade 3 or 4 ALT elevation for either men or women, and the only independent risk factors by multivariate analysis were HBV or HCV coinfection (odds ratio 3.92), or elevated ALT levels at baseline (OR 4.84). A prior AIDS diagnosis, a CD4 count above 250 cells/mm3, or being new to treatment did not increase the risk.


Two-Drug ART With TDF/EFV Less Effective Than Triple-ART

A team of French investigators has found a two-drug maintenance regimen of TDF/EFV to be less effective than a three-drug regimen containing the same two drugs plus 3TC over 48 weeks of followup.15 As a possible way of reducing long-term toxicities associated with NRTIs (e.g., lipodystrophy), the COOL study specifically looked at the effectiveness and toxicity of 3TC as part of one specific antiretroviral drug regimen. In this study, researchers at various sites in France took participants already on successful ART, and switched them to either a standard three-drug regimen -- TDF/3TC/EFV -- or a simplified regimen of only TDF and EFV.

To enter the 48-week trial, patients needed to have already been on a stable treatment regimen for at least three months, with a viral load below 50 copies/mL, and no history of treatment failure. They needed to weigh over 45 kg, and to show no significant toxicities at the time of entering the trial. Since TDF may be toxic to the kidneys in people with reduced kidney function, laboratory markers of kidney health had to be normal (creatinine clearance over 60 ml per minute). There were no restrictions on CD4 count.

The COOL study enrolled 143 patients, who were randomized to receive either TDF/EFV/3TC, or TDF/EFV. Characteristics of the two groups were very similar, with the following overall average values: 40 years of age, 69kg, CD4 count of 473 cells/mm3, and 3.7 years on ART (43.5% NNRTI-based, 45.5% PI-based, 71% including ZDV/3TC). Twenty-eight percent of the participants were female.

Intent-to-treat (ITT) analysis included all 143 original participants; cases where data was missing for any reason (including those who dropped out of the study) were classified as treatment failures. Table 2 reflects results by both methods.


Table 2. Two- Versus Three-Drug Maintenance for 48 Weeks

Table 2. Two- Versus Three-Drug Maintenance for 48 Weeks


Six participants were "lost to follow-up" in the TDF/EFV arm, but only two in the TDF/EFV/3TC arm. Somewhat oddly, all four dropouts due to side effects were in the TDF/EFV arm. (No kidney toxicity or drop in blood phosphate levels was seen.)

All three of the virologic failures were also in the two-drug, TDF/EFV arm: all three of these patients acquired NNRTI resistance mutations. (One case was likely due to very poor treatment adherence, but the adherence levels for the other two were not known.) There was no explanation as to why more side effects and dropouts would be seen in the group taking fewer medications.

The researchers concluded that, "TDF/3TC/EFV demonstrates an optimal success rate (97%) as a maintenance regimen when compared to TDF/EFV (82%). Switching to a ... [TDF]-based regimen can significantly improve lipid profile even when lipid [levels] are within the median normal range at baseline. Other improvements in biological parameters were observed following a switch from [twice-daily] HAART to TDF-based HAART."


Reduced LPV/r Soft-Gel Capsule Dose Effective in Kaledose

French researchers conducting the Kaledose study have found that it may be possible to reduce the standard dosing of the LPV/r soft-gel capsule from three capsules twice daily to two capsules twice daily. However, viral load blips were frequently seen in patients taking the reduced dose, and therapeutic drug monitoring (TDM) is recommended.16

Although the new hard tablet formulation of LPV/r has recently become available in the United States and the European Union, the LPV/r soft-gel capsule is still being used elsewhere in the world until the new formulation becomes available. The drug's manufacturer, Abbott Laboratories, has filed for registration of the new tablet formulation in countries in Africa, Asia and Latin America.

This trial only studied the soft-gel formulation of LPV/r, which contains 133.3 mg LPV and 33.3 mg RTV in each capsule. The standard dose is three capsules twice daily, providing 400 mg of LPV boosted with 100 mg of RTV twice a day. The Kaledose study examined two soft-gel capsules twice daily, providing 266.6mg of LPV and 66.6mg of RTV twice a day.

For treatment-naive patients, the recommended LPV trough concentration (Cmin) is 3,000 ng/mL. Over half the patients in a database kept by the study investigators had LPV Cmin levels of 5,000 ng/mL or more. This led researchers to believe that lower doses of LPV/r might be safe and effective, and lead to fewer side effects.

The study group enrolled adults on an antiretroviral regimen that included LPV/r. None had ever taken a PI. (Some had previously been on NNRTI-based regimens; none were taking NNRTIs during this study.) All had maintained an undetectable viral load (less than 50 copies/mL) for at least three months, and were tested to ensure they had LPV Cmin levels of more than 5,000 ng/mL. Average CD4 count was 346 cells/mm3, average age was 44.6 years, and patients had been HIV-infected an average of 5.2 years.

Out of 33 initial participants, five dropped out during the study, leaving a total of 28 at the 48-week endpoint. The reduced dose resulted in lower trough LPV concentrations -- an average of 4,319 ng/mL, down from 7,363 ng/mL; with 1,427 ng/mL being the lowest level observed. At the end of the study, three out of the 28 participants had detectable viral loads (80 copies/mL, 160 copies/mL, and 1,842 copies/mL).

However, over the course of the study, the investigators reported that a proportion of participants experienced viral load blips that returned to below 50 copies/mL two weeks later. Unfortunately, the researchers' report is inconsistent, and either eight out of the 28 participants experienced a total of 13 viral load blips, or 13 of the 28 participants experienced a total of 18 viral load blips. None of the blips were greater than 2,000 copies/mL, and the majority of the blips were between 51 and 100 copies/mL. The researchers state that they did not find any significant differences in LPV Cmin levels in the patients whose viral loads blipped; in fact, they were not able to find any specific factors that identified the patients at risk of blips.

Over the 48 weeks, blood triglyceride levels went significantly down (from an average of 1.73 mmol/L to less than 1.4 mmol/L). Two episodes of gastrointestinal problems were reported. A more detailed report on side effects and quality of life was not presented; the analysis is still ongoing.

The researchers concluded that, "a reduced dosing of LPV/r in patients without previous failure of PI containing regimen[s] and with Cmin >5,000 ng/mL is associated with a sustained virological response. Nevertheless, this strategy is associated with episodes of [viral load blips]. Therapeutic drug monitoring and [viral load] control is recommended in this type of strategy."


Needle-Free ENF Administration ISRs

A small eight-week study of a needle-free injection device for enfuvirtide (ENF) has shown the device to be as effective as injection by needle, without causing as much pain, discomfort, and swelling.17 Because ENF is composed of a very large drug molecule, it cannot be taken orally since the digestive system would break the drug down into smaller molecules that would not be effective against HIV. Until now, ENF has been taken by twice-daily subcutaneous injections that very frequently cause injection site reactions (ISRs).

The drug is prepared in the same way no matter which injection method is used -- a prepared powder is dissolved in sterile water to produce an injectable liquid. When 27-gauge needles are used to inject the liquid subcutaneously, the entire dose forms a bubble below the skin surface, which tends to produce hard nodules at the injection site and prevents the site from being used again until the nodule has cleared.

Instead of needles, a hand-held needle-free injection device (NFID) called the Biojector B2000 can also be used to administer ENF. The needle-free injection device uses pressurised gas to blast the liquid below the skin surface, thus avoiding the need for needle punctures, and dispersing the drug more evenly over a larger area. While the Biojector B2000 has been in use for some time, it has not been well studied in randomized clinical trials.

The study used a crossover methodology to compare both injection methods for participants who were beginning ENF for the first time. Participants were randomized to begin with either the Biojector B2000, or standard 27-gauge needles. After four weeks, they switched over to the opposite method. All participants who completed the study had therefore tried both methods, and were able to compare their satisfaction levels, preference, and adherence. Minimum blood concentration levels were also monitored to ensure that effective ENF doses were being delivered.

Fifty-eight people were enrolled, about half of whom were Caucasian and 85% of whom were white, an average of 43 years old, with a median of 203 CD4 cells/mm3 and 4.6 log viral load. (Fifty-four percent had previous experience with self-injection.) Of these, 49 went on to actually start taking ENF; data on at least one dose was available for 48, and 39 completed the full eight-week study.

Drug concentration levels were similar for both methods, especially when nonadherent patients were left out of the comparison. The average minimum concentration of ENF achieved by the Biojector B2000 was 2,038 ng/mL, and 2,204 ng/mL by subcutaneous needles.

Although almost all participants had some degree of ISR no matter which method was used, the reactions were considerably less severe with the Biojector B2000. Participants overwhelmingly (84%) rated the Biojector B2000 as the preferable method. The researchers concluded that "[needle-free injection device] administration of [ENF] resulted in a substantially lower incidence of painful nodules ... was preferred by most patients over standard [27-gauge needles], and is generally safe and well-tolerated."


Scoping Out the Newer ARVs on the Block

No DRV Response Difference by Prior PI Use in POWER

The new boosted PI darunavir (DRV) has already proven to be more powerful than other boosted PIs when taken by highly ART-experienced patients. Combined results from three related clinical trials have now confirmed that DRV is equally effective, regardless of which PI has been used previously.18

Much of the data on DRV are drawn from several ongoing multi-site trials. For the purposes of this study, data from three of these randomized trials -- POWER 1, 2, and 3 -- was combined. These three trials all studied similar groups of people: participants were on failing regimens, with viral loads over 1,000 copies/mL. They also had experience with NRTIs, NNRTIs, and PIs, and had developed at least one PI resistance mutation. On starting the study, all participants received a background antiretroviral regimen that was optimized by resistance testing, plus 600 mg DRV and 100 mg RTV twice daily. The new combinations may or may not also have included ENF; none contained NNRTIs.

The study looked at virological response to the new regimen after 24 weeks (Table 3). Specific comparisons were made between those whose previous (failing) regimen had contained tipranavir (TPV), LPV, and FPV.


Table 3. 24-week Response to DRV/r After PI Failure

Table 3. 24-week Response to DRV/r After PI Failure


Results were very similar for the study overall, and the three PI-specific groups. In the overall study (n=458), the average viral load drop was of 1.74 log and 42% became undetectable. The average viral load drop in the TPV group (n=51), LPV group (n=192), and FPV group (n=74) was 1.64 log, 1.72 log, and 1.66 log, respectively. Forty-four percent became undetectable in the TPV group, versus 40% and 42% in the LPV and FPV groups, respectively.

The study also compared the effectiveness of boosted DRV to other control PIs (CPIs). In the set of participants studied (131 on DRV-containing regimens, 124 on CPIs), 45% and 12%, respectively, achieved viral loads of less than 50 copies/mL after 24 weeks. Responses were better in those who showed genotypic susceptibility to at least one CPI at baseline (24% versus 7% in those resistant to all CPIs). Among the CPIs, FPV was the most successful, leading to undetectable viral loads in 16% of those on an FPV-containing regimen.

Researchers concluded that DRV "showed greater HIV RNA reductions and CD4 count increases over the [control PIs (CPIs)] used by the control group, regardless of CPI used, type of boosting (single or double RTV-boosted PI regimen), and baseline susceptibility." They added that, "the PI-based regimen at screening did not affect the subsequent virologic response to [DRV/RTV] 600/100 mg bid plus [an optimized background regimen] after 24 weeks of treatment."


MK-0518 Stalls Resistant HIV, Causes No Lipid Increase at 24 Weeks

In heavily treatment-experienced patients with few -- or no -- antiretroviral drugs available as an option for a salvage regimen, the integrase inhibitor MK-0518 stalled HIV impressively.19 The investigational drug worked even better when ENF-naive patients could start it in combination with ENF. MK-0518 inhibits the activity of integrase, an HIV enzyme that allows the virus to insert its genetic material into the DNA of human T-cells.

Researchers from Europe and the United States randomized 178 treatment-experienced patients to 200 mg, 400 mg, or 600 mg of MK-0518 twice daily, or placebo, plus an optimized background regimen picked on the basis of resistance tests and treatment history. But the researchers could do little or nothing to optimize the new regimens of most study participants. About half of those enrolled had a phenotypic sensitivity score (PSS) of 0 to all antiretroviral drugs, meaning the Phenosense GT assay rated their virus resistant to every available drug except MK-0518. According to this same test, about 90% of study participants did not have a single active PI to put in their new regimen.

When patients signed up for the study, their viral loads averaged 40,000 copies/mL to 63,000 copies/mL across the study arms. Average CD4 counts stood at 200 cells/mm3 to 245 cells/mm3 in the three MK-0518 arms and at 274 in the placebo group.

By study week 24, 10 participants (23%) had quit the 200-mg arm, eight (18%) had left the 400-mg arm, eight (18%) the 600-mg arm (18%), and 31 (69%) the placebo arm. Three dropouts in the MK-0518 arms and 1 in the placebo arm resulted from clinical problems or side effects. Lack of efficacy caused the other 49 dropouts.

A 24-week noncompleter-equals-failure analysis figured that about 70% in all three MK-0518 groups had a viral load below 400 copies/mL, compared with fewer than 20% in the placebo group. While 57% to 67% in the MK-0518 arms had a 24-week load below 50 copies/mL, only 14% in the control arm hit that mark. About 80% taking MK-0518 at any dose had at least a 1-log (10-fold) viral load drop by week 24, compared with 18% in the placebo arm. Viral load declines averaged about 2 log (100-fold) with the integrase inhibitor and 0.4 log with placebo plus other background drugs. Among people who started the trial with a phenotypic sensitivity score of 0, 54% to 62% randomized to MK-0518 had a 24-week viral load under 400 copies/mL, while no one in the placebo group with a baseline score of 0 got below 400 copies (Table 4).


Table 4. Response to MK-0518 by Baseline PSS

Table 4. Response to MK-0518 by Baseline PSS


As in previous salvage therapy studies, including ENF in the regimen increased chances of virologic response. Among people in the placebo arm, the percentage with a 24-week viral load below 400 copies/mL rose from about 15% without ENF to about 30% with the injectable drug. In the MK-0518 arms the response rate climbed from about 60% without ENF to 90% or more with ENF. These findings underline the advantage of waiting until one has at least two potent antiretroviral drugs for a salvage regimen -- if at all possible -- rather than adding new drugs one at a time to already enfeebled antiretroviral drugs.

Grade 3 or 4 lab abnormalities proved uncommon and their rates were similar in the MK-0518 and placebo groups. The researchers reported four serious clinical setbacks: one stroke in the placebo group, one case of acute pancreatitis after two doses in the 200-mg MK-0518 group (attributed to the background regimen), one case of lipoatrophy, and one death from metabolic acidosis and renal insufficiency.

In a separate dose-ranging study with treatment-naive patients, participants receiving MK-0518 experienced no significant increases in total cholesterol and triglycerides (Table 5).20 The study compared four doses of MK-0518 with EFV in 184 treatment-naive patients also receiving TDF and 3TC.


Table 5. Lipid Level After 24 Weeks of MK-0518 or EFV

Table 5. Lipid Level After 24 Weeks of MK-0518 or EFV


Baseline lipid levels were comparable across the five study arms, at around 160mg/mL for total cholesterol and between 110 mg/dL and 155 mg/dL for triglycerides. After 24 weeks on treatment, very slight declines in lipid levels were observed in the MK-0518 recipients at all doses (with the exception of HDL cholesterol), but in the EFV group all lipid levels rose. The only statistically significant difference was seen in LDL cholesterol, where the EFV group had an increase of approximately 5mg/dL while slight declines were seen at all MK-0518 doses (P

Plugging CCR5 With a Monoclonal Antibody

Most attention on blocking CCR5 coreceptors has focused on the CCR5 antagonists -- aplaviroc (no longer being developed), maraviroc, and vicriviroc -- and this year's ICAAC featured some intriguing studies on all three of these investigational drugs. But a humanized IgG4 monoclonal antibody currently under study also keeps HIV off CCR5 receptors and boosts the power of traditional antiretroviral drugs.21 Twenty-four weeks of serial passage pressure did not promote emergence of mutations conferring resistance to this agent, but that does not mean HIV cannot find a way to outmaneuver the monoclonal antibody. A disadvantage of this monoclonal antibody, still enigmatically tagged CCR5mAb004, is that it requires intravenous infusion.

Fifty-four ART-naive patients with virus that homes exclusively to CCR5, viral loads of more than 5,000 copies/mL copies, CD4 counts of more than 250 cells/mm3 were randomized to a single infusion of 0.4 mg/kg, 2 mg/kg, 8 mg/kg, 20 mg/kg, or 40 mg/kg of CCR5mAb004 or placebo. The 2-mg/kg-dose raised a moderately severe urticarial rash in two people. After that the researchers pretreated people with oral diphenhydramine and no more rashes flared. No one experienced grade 3 or 4 treatment-related problems.

CCR5mAb004 has a slow onset of action -- three to four days -- while it coats CCR5 receptors. But one infusion lasts a long time. The monoclonal antibody eventually saturated more than 80% of receptors 14 to 28 days after infusion of 8 mg/kg or higher doses. The researchers calculated a five- to eight-day half-life for CCR5mAb004. Maximum concentration of the monoclonal antibody was dose-proportional (the higher the dose, the higher the concentration), and area under the concentration-time curve (AUC) was more than dose-proportional.

More than half of the participants who took the higher doses of CCR5mAb004 had at least a 1-log (10-fold) drop in viral load at day 14 (Table 6). Those who began therapy with a lower pre-treatment viral load had a better chance of knocking their viral load down farther: Pre-treatment loads averaged 4.0 log (10,000 copies/mL) in participants with more than a 1-log drop and 4.4 log (about 25,000 copies/mL) in those with less than a 1-log drop (P= 0.02). The monoclonal antibody's 90% inhibitory concentration was significantly lower (better) in patients who had at least a 1-log viral load dip (31.3 µg/mL) than in those who did not (87.5 µg/mL) (P=0.0388).


Table 6. Day 14 Response to an Anti-CCR5 Monoclonal Antibody

Table 6. Day 14 Response to an Anti-CCR5 Monoclonal Antibody


Notably, HIV preference for CCR5 changed in five people after one day of treatment. Because the Monogram Biosciences assay used to determine coreceptor preference (tropism) still has shortcomings, it is impossible to say whether these coreceptor shifts resulted from infusion of the monoclonal antibody or whether they simply reflect the assay's inadequacies. Whatever the explanation, none of the five people with changing tropism had a good virologic response to CCR5mAb004, even though four of them got either the 20- or 40-mg/kg dose.

How this infused monoclonal antibody would be integrated into an oral antiretroviral regimen and whether it can compete with oral CCR5 antagonists remain to be determined. This year's ICCAC provided an insight into oral CCR5 antagonists -- interestingly via results of a study of one CCR5 antagonist whose wings were clipped earlier this year. Development of the investigational CCR5 antagonist, aplaviroc, was suspended when a few patients in its study suffered severe liver toxicity. But an aplaviroc study may hold clues to the efficacy of the two remaining CCR5 antagonists: maraviroc and vicriviroc.

Data from the aplaviroc study indicated that resistance to aplaviroc in patients with virologic failure could prove hard to spot with standard viral-population-based testing.22 Clonal analysis -- which looks at a wide array of clones created from HIV isolates -- was conducted in 10 ART-naive patients who began treatment with aplaviroc plus LPV/r and endured virologic failure, defined as less than a 1-log (10-fold) drop in viral load by treatment week 4, a confirmed viral load above 400 copies/mL after a sub-400 copies/mL load, or more than a 0.5-log viral load climb from the lowest recorded load.

Testing on the population level detected no drop in susceptibility to either aplaviroc or LPV/r. But clonal analysis uncovered reduced susceptibility to aplaviroc in fewer than half of the clones derived from six of the 10 patients. The researchers also found shifts in coreceptor affinities from R5-only virus to R5/X4-mixed virus in two of these 10. But phylogenetic analysis suggested that one person had mixed-tropic virus before treatment began. The study did not turn up mutations in the viral envelope gene that correlate with reduced susceptibility to aplaviroc.

In another study, researchers reported cell study results gauging how avidly four CCR5 antagonists bind to their target receptor, and how long they stick to the target after binding.23 Maraviroc and aplaviroc bound CCR5 more tightly than vicriviroc (Table 7). But vicriviroc clung to CCR5 almost twice as long as maraviroc. Aplaviroc won the durability contest, plugging CCR5 receptors twice as long as vicriviroc.


Table 7. CCR5 Antagonist Receptor Affinity and Disassociation

Table 7. CCR5 Antagonist Receptor Affinity and Disassociation


Vicriviroc's slow receptor dissociation rate supports its once-daily dosing schedule; ongoing maraviroc trials are testing both once- and twice-daily dosing. Whether this dissociation advantage and potential dosing plus for vicriviroc translate into a clinical edge can be determined only in a head-to-head comparison with maraviroc.


Novel NRTI Active Against HIV in Monotherapy Study

After Toronto, 46th ICAAC Offers Back to Basics
The investigational NRTI elvucitabine demonstrated potent and prolonged anti-HIV activity in a seven-day monotherapy study.24 Elvucitabine (also known as L-Fd4C) is an L-cytosine nucleoside analogue. A small study reported at last year's ICAAC showed that various doses of elvucitabine plus LPV/r suppressed HIV RNA by as much 2 log10 copies/mL over 21 days. That study demonstrated the short-term safety of elvucitabine, but was not able to determine how much of the observed antiviral effect was attributable to the new drug and how much to LPV/r. Accordingly, researchers then carried out a study of elvucitabine used as monotherapy.

The present Phase II double-blind study presented on at this year's ICAAC included 24 HIV-positive participants who were randomly assigned to receive 10 mg once-daily elvucitabine or placebo. After seven days on elvucitabine monotherapy, these patients were given LPV/r for an additional 21 days in order to reduce the risk of resistance, since elvucitabine remains in the body for a prolonged period.

All participants but one were men, and all but one was white; the average age was about 40 years. The presenter noted that future multicenter trials would aim to enroll a more diverse study population. Baseline characteristics were generally similar in both arms, but participants randomized to the elvucitabine group had a slightly lower CD4 count than those in the placebo arm (mean 320 cells/mm3 versus 403 cells/mm3). The mean viral load level was about 4.75 log10 copies/mL. Patients had minimal previous ART experience, and genotypic testing showed that they did not have mutations associated with resistance to elvucitabine or LPV/r (M184V, M184I, D237E).

By Day 7, viral load declined by an average of 0.85 log10 copies/mL from baseline in patients taking elvucitabine, compared with essentially no change in the placebo group (P3 versus 9 cells/mm3, respectively. Viral load continued to decrease even after discontinued use of elvucitabine, but the decline became less pronounced as elvucitabine concentrations dropped. On Day 21 (14 days after the last elvucitabine dose), the maximal viral load decrease was 1.73 log10 copies/mL, before rising again.

Pharmacokinetic analyses showed that the overall half-life of elvucitabine was about 100 hours, and there were still detectable concentrations in plasma and peripheral blood mononuclear cells at Day 21. Maximum concentrations and maximum trough levels of plasma elvucitabine were attained on the final day of dosing, but concentrations remained above the IC50 (the level at which viral replication is reduced by 50%) for up to 14 days after discontinuation.

Overall, elvucitabine was well tolerated. No major safety issues were identified, and the emergence of virus with resistance to elvucitabine or LPV/r was not observed. The researchers concluded that, "these results confirm that elvucitabine monotherapy demonstrates significant antiviral activity over seven days of dosing." They added that the drug's long plasma and intracellular half-life and concentration-dependent efficacy "may provide a better barrier to resistance than antiviral agents with short half-lives."


One-Two Punch From the DRV/TMC125 Duo

Two single-center studies suggest that DRV and the investigational NNRTI etravirine (TMC125) could be a formidable duo for patients resistant to other drugs in those classes.25 Thirteen of 15 patients in these small, nonrandomized studies -- one presented at this year's ICAAC, the other at the 16th International AIDS Conference -- saw their viral loads dip under 50 copies/mL within 24 weeks of starting DRV and etravirine with a clutch of NRTIs and, sometimes, ENF.

British researchers paired DRV and etravirine in 12 patients with woeful resistance records. Two withdrew consent for personal reasons. Among the remaining 10, the median number of primary PI mutations stood at four (range 0 to five), the median number of NNRTI mutations at two (range 0 to six), and the median number of NRTI mutations at seven (range two to nine). Median fold-change in susceptibility to PIs ranged from 0.4 to 137.6 (1.25 for DRV) and to NNRTIs from 0.6 to 104.9 (1.25 for etravirine). Six of 10 participants had already tried TPV and emtricitabine (FTC); only two patients started FTC as a new drug in this study. Everyone took 200 mg of etravirine twice daily, 600/100 mg of DRV/r twice daily, and two or more NRTIs.

After 24 weeks, nine of 10 participants had a viral load under the 50-copy/mL mark. The tenth had a viral load of 722 copies/mL, which dwindled to 59 copies/mL by week 32. Median drop in HIV RNA log copies/mL measured 2.7 (range 2.3 to 3.9), and median CD4 gain stood at 113 cells/mm3 (range 41 cells/mm3 to 268 cells/mm3). No one had a serious clinical setback or dangerous lab reading. Possible treatment-related side effects included mild diarrhea in one patient, headache in one, and rash in one. All problems resolved without a change in drugs or dosing.

Editor's Note: This article is compiled from various reports which have been adapted and reprinted with permission from www.aidsmap.com and www.natap.org.


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