Table of Contents
Acute HIV Infection and the Sexual Transmission of HIV
An increased rate of syphilis in men who have sex with men (MSM) in the United States,1 plus a possible increase in new HIV infections,2 clearly mean that our HIV prevention efforts are failing. This study underscores the importance of increasing HIV awareness among high-risk populations, and awareness of the role played by recently infected persons in transmitting HIV to others.
Pilcher CD, Tien HC, Eron JJ, et al, for the Quest Study and the Duke-UNC-Emory Acute HIV Consortium. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis. May 15, 2004;189(10):1785-1792.
This interesting study from North Carolina researcher Christopher Pilcher et al assessed concurrent blood and semen HIV-1 concentrations in 30 men experiencing acute HIV infection who were participating in 2 large, acute-infection cohorts. All of the semen samples were obtained 14 to 84 days (median 38 days) after the estimated time of infection. Semen HIV-RNA levels in that group were significantly higher (mean 4.1 log copies/mL) than those in a comparison group of patients with chronic HIV infection (mean 3.49 log copies/mL; P = .04). Semen levels were significantly higher during the initial stage than in the later stages of acute infection (P<.01). In addition, over time, acute-infection semen and blood HIV levels were significantly correlated.
The authors creatively constructed a model examining HIV-1 levels in semen. This model was used in conjunction with a previously published probabilistic model of male-to-female transmission of HIV-1 as a function of R5 HIV levels in ejaculate and CCR5 receptor cell levels in cervicovaginal tissues.3 This model assumes that R5 (or macrophage-tropic) HIV is responsible for most heterosexual transmission of HIV, and that the R5 receptor density on the surface of susceptible cervicovaginal tissue relates to the risk for HIV acquisition.
The results of this study confirm that men are hyperinfectious during acute HIV infection due to increased genital shedding of HIV. The model suggests that the probability of HIV transmission is 8- to 10-fold higher 20 days after infection (when HIV-RNA levels peak) than after the viral set point has been reached (>day 54 after infection).
Depending on the frequency of intercourse, men could infect 7-24% of their susceptible female partners during the first 2 months of their HIV infection. (This study just looked at heterosexual transmission models.) The rate of transmission would be even higher in the presence of a sexually transmitted disease (STD) in either partner.
An additional conclusion from the study was that in the absence of an STD, HIV viral dynamics and blood levels mirror those in the genital tract. To prevent additional HIV infections, this study clearly emphasizes how critical both behavioral and antiretroviral interventions are for the recently infected.
Prevention as Part of Clinical Care
Clinicians are in a unique position to prevent HIV infections. Given the increased rates of syphilis and new HIV infections among MSM in the United States, it is important that clinicians become involved. But how do we incorporate prevention counseling into the typically hectic setting of a clinic? The following timely study from 6 Californian clinics and the U.S. Centers for Disease Control and Prevention provides a useful blueprint for clinic-based HIV prevention counseling.
One concern I have with the practical implications of this study is that adding even another 3 to 5 minutes per patient would be difficult in already overstretched clinic schedules. Ideally, having another healthcare provider responsible for the prevention message would be more expedient, although, in our currently collapsing healthcare system, it's unlikely we'll be able to find the funds to pay for that.
Richardson JL, Milam J, McCutchan A, et al. Effect of brief safer-sex counseling by medical providers to HIV-1 seropositive patients: a multi-clinic assessment. AIDS. May 21, 2004;18(8):1179-1186.
How, or even whether, to include safe-sex counseling during HIV clinic visits are subjects that have never received enough attention. In this study, investigators recruited 585 sexually active, HIV-infected persons seen at 6 HIV clinics in California. Three different approaches to safe-sex counseling were used (2 clinics used each of the 3 approaches).
One approach used something called "gain-framed" counseling that emphasized the positive benefits of practicing safer sex (i.e., emphasizing the benefits for patients of protecting themselves and others from STDs or superinfection with other strains of HIV). Another approach used a "loss-framed" counseling strategy that emphasized the negative consequences of unsafe sex (i.e., encouraging patients to make choices that do not put themselves or others at risk). The third approach, termed "attention control," emphasized adherence to antiretroviral therapy (ART).
Providers and clinic staff were trained to deliver the counseling intervention that the researchers had randomly assigned to their clinic. The intervention was then delivered during a 10- to 11-month period in 1999-2000. A trained interviewer made baseline behavior assessments prior to the intervention period. The cohort was then reassessed during a period of up to 7 months after the intervention ended.
The intervention was called "Partnership for Health," emphasizing the importance of the provider-patient relationship in helping the patient to stay as healthy as possible. The counseling period, which occurred during regular clinic encounters, was brief (3 to 5 minutes) and was given at all visits except those related to acute medical problems. Every patient received similar written materials. The primary outcome measure was the self-reported rate of unprotected vaginal or anal intercourse with any partners during the previous 3 months. For subjects who had just 1 baseline sexual partner, there were no significant changes after the intervention for any of the 3 groups. Among subjects with 2 or more baseline sexual partners, the rate of unprotected vaginal or anal intercourse decreased by 4% in the attention-control group, increased by 10% in the gain-framed group (P = .64), and decreased by 38% in the loss-framed group (P<.001).
The authors note4 that 36-63% of all HIV-infected adults in the United States receive ongoing medical care, and that this population is responsible for transmitting a significant percentage of HIV infections in the United States, powerfully underscoring the need to carry out more prevention interventions in HIV clinics.
According to the results of this study, the loss-framed counseling technique, as employed by a provider, appears to capture a patient's attention more strongly than the other 2 approaches. Combining both the gain- and loss-framed techniques is another approach that has not been studied much in this setting, which the paper itself suggests is worth trying!
Since relatively small numbers of heterosexual men and women were included in the study, the results are most applicable to MSM. The researchers concluded that counseling that emphasizes the risks associated with unsafe sex may help people with baseline risky profiles to avoid acquiring other STDs or strains of HIV, and avoid transmission to others. The authors note that their study needs to be followed up with additional research, since there is a paucity of information about how to effectively counsel patients to practice safe-sex behaviors in a variety of settings and populations.
Negative Results From a Quality-Improvement Study
Measuring and improving quality of care has become critical in many areas of medicine. There has also been much discussion regarding the fact that negative results do not get published at the same rate as studies demonstrating a positive effect of quality-of-care interventions. This study examined the effectiveness of a program that was designed to increase rates of quality-of-care measures at clinics receiving funding from the Ryan White CARE Act.
Landon BE, Wilson IB, McInnes K, et al. Effects of a quality improvement collaborative on the outcome of care of patients with HIV infection: the EQHIV study. Ann Intern Med. June 1, 2004;140(11):887-896.
Landon and his group used 44 intervention clinics and 25 control clinics matched by general clinic characteristics. Measures examined included use and effectiveness of highly active antiretroviral therapy (HAART), screening and prophylaxis, and access to care. The researchers looked at the care of 9,986 patients.
The differences in quality of care after the intervention were not significant. The proportion of patients with suppressed viral loads increased from 40 to 51% in the intervention group, compared with an increase from 44 to 49% in the control group (P = .18). Details are lacking about some of the actual interventions used in this study, but I suspect that many of them fall within the realm of community standards of care, so the difference between the intervention and control groups may become blurred. The authors suggest that additional research is needed to achieve better results by improving methods of teaching and implementing quality-improvement projects.
One of the biggest problems with this study involved the quality indicator(s) used. Having worked exclusively at public hospitals and clinics serving an indigent patient population with a multitude of unmet housing, mental health and chemical dependency needs for many years, I have been cautious about starting HAART before a patient is ready or needs such therapy. In addition, it is unclear whether the pharmacies and clinics that care for this type of patient can properly monitor adherence for a large number of these patients simultaneously.
The quality marker used in this study that was particularly troublesome related to the use of HAART in patients with CD4+ cell counts <500 cells/mm3 and viral loads >10,000 copies/mL. Although the use of HAART for these patients was not the practice for many clinicians, it was part of the recommendations for treatment from 1996-2000 (the study was done in 2000). More recent recommendations from the International AIDS Society-USA Panel5 and the U.S. Department of Health and Human Services (DHHS) (www.aidsinfo.nih.gov/guidelines) have shifted these recommendations, based on accumulated experience and study results, to a more conservative treatment philosophy.
In addition, the other "quality markers," such as tuberculosis screening, hepatitis C screening, and use of vaccinations, may have little data indicating that such tests or interventions clinically benefit key segments of the HIV-infected population (such as patients with CD4+ cell counts <200 cells/mm3).
Now that there are waiting lists in many states for HIV-infected patients to receive ART, it is imperative to critically examine how to optimally use the available but limited resources to protect the health of those at risk for HIV-related morbidity and mortality. Regional HIV-related morbidity and mortality statistics would be better markers for evaluation of the Ryan White program than simply tabulating the percentage of patients on HAART or those who had a particular laboratory test obtained. It is my opinion that many quality-improvement projects are imposed on an already busy and often beleaguered staff, so that there are neither the funds nor the staff to do a good job. Given the increasingly underfunded state of HIV care in the United States, the window for high-quality studies of this nature under the auspices of the Ryan White CARE program may have closed, as the funds must be used to provide necessary antiretroviral drugs in the setting of budget shortfalls.
Directly Observed Therapy in the United States?
Studies of the effectiveness of ART have consistently shown that high compliance rates result in better outcomes.6 In many real-world settings, the effectiveness of HAART seems lower than in published clinical trials in which pre-selected patients, chosen for their likelihood to be compliant, are followed in well-staffed research clinics.
Because directly observed therapy (DOT) has been shown to be effective in the control and treatment of tuberculosis,7,8 there has been interest in adapting DOT strategies for the treatment of HIV infection. One problem with indefinite DOT, which would be necessary since HIV infection is incurable, is the high cost of healthcare workers in the United States when funding is already strapped in many public and private settings.
Paul Farmer has achieved well-deserved fame for his humanitarian and clinical efforts in Haiti, and his writings regarding the interaction of poverty and health. He helped develop a DOT-HAART program in rural Haiti using people they call "accompagnateurs" -- low-cost healthcare workers -- to promote maximum adherence. The accompagnateur also provides psychosocial support and links patients to clinical staff and other available resources. In this article, Farmer summarizes his experience with the Haitian program and a similar program in Boston for patients with drug-resistant HIV disease who had experienced failure during unsupervised therapy.
Behforouz HL, Farmer PE, Mukherjee, JS. From directly observed therapy to accompagnateurs: enhancing AIDS treatment outcomes in Haiti and in Boston. Clin Infect Dis. June 1, 2004;38(suppl 5):S429-S436.
The HIV Equity Initiative in Haiti built on their ongoing tuberculosis therapy program, which utilized DOT with an extensive network of community health workers. The accompagnateur is the centerpiece for the tuberculosis therapy and DOT-HAART programs.
Farmer emphasizes that the accompagnateur's role is more complex than simply watching patients take pills. The accompagnateurs are respected in their community and serve as the key link between the patient and the clinic.
At the patient's request, an accompagnateur is selected from among the clinic staff or hired from the community. In Haiti, the majority of accompagnateurs are peasant farmers or market women. They receive training on clinical aspects of HIV, confidentiality and ways to provide emotional support. They observe patients taking their HIV medications once or twice daily.
The data provided in this article are descriptive, providing only general observations and results. The Haitian program, which managed 100 patients in this manner, was outstanding, with an impressively low (<2%) dropout rate.
It is immensely appealing to try and use potentially lower-cost personnel to achieve better outcomes with challenging patient populations. In future articles, I look forward to further details about how the accompagnateur concept could be set up in U.S. sites, and how such programs could be funded and sustained.
Histoplasmosis Maintenance Therapy Can Be Stopped After Immune Recovery
In the pre-HAART era, my patients who succumbed to AIDS suffered through an average of 4 to 5 AIDS-defining conditions. Successful treatment of one opportunistic infection seemed only to allow survival to the next one, as a patient's immune system seemed permanently stuck in reverse. I still remember the excitement of the arrival of potent ART in 1996. The revolution of that moment was not only that a patient's HIV level could be decreased to the detection limit, but that CD4+ cell counts could be increased to never-before-seen levels. Sick patients got better, and at-risk patients did not get sick.
As time went on, successive studies9,10 demonstrated that adequate immune recovery would allow the discontinuation of prophylaxis or maintenance therapy for conditions such as Pneumocystis, Mycobacterium avium and cytomegalovirus. This study, led by Mitch Goldman from the AIDS Clinical Trials Group (ACTG), reports that maintenance therapy for disseminated histoplasmosis can also be safely stopped after adequate immune recovery.
Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis. May 15, 2004;38(10):1485-1489.
This was a prospective observational study conducted by the ACTG to evaluate the safety of stopping maintenance therapy for disseminated histoplasmosis among HIV-infected patients after at least 12 months of antifungal therapy and 6 months of HAART. All patients had documentation of prior disseminated histoplasmosis. Details of ART regimens or nadir CD4+ cell counts were not provided. Negative results of fungal blood cultures, urine and serum Histoplasma antigen levels <4.1 units, and CD4+ cell counts >150 cells/mm3 were required. Thirty-two subjects were enrolled, with a median CD4+ cell count of 289 cells/mm3. No relapse of histoplasmosis was observed after a median follow-up of 24 months -- a rate of zero cases per 65 patient-years. The median CD4+ cell count at the end of the study was 338 cells/mm3.
The authors reasonably concluded from this study that maintenance therapy for disseminated histoplasmosis can be safely stopped for patients with similar characteristics. That is good news for HIV-infected patients in the Midwestern United States where histoplasmosis is endemic.
What Happens After PI Failure?
One of the major issues currently facing clinicians is the selection of first-line HIV therapy. This first choice is critical in planning future treatment options. If a patient starts on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen and fails, for example, the presumption is that a protease inhibitor (PI)-based regimen (generally boosted with ritonavir [RTV, Norvir]) will usually be successful as a follow-up regimen. However, there are few published studies looking at long-term outcomes after failure of initial NNRTI-based therapy.
Alternatively, if the initial regimen is PI-based, it is even less clear how successful the subsequent regimen will be. Obviously, it depends on many factors, such as available drugs, specific drugs used in the initial regimen, adherence habits and amounts of resistance. This study reviews reports published in the HAART era (Jan. 1, 1997 to May 31, 2003) to examine what happens when patients are switched to a follow-up regimen after the failure of an initial PI-based regimen.
Losina E, Islam R, Pollock AC, Sax PE, Freedberg KA, Walensky RP. Effectiveness of antiretroviral therapy after protease inhibitor failure: an analytic overview. Clin Infect Dis. June 1, 2004;38(11):1613-1622.
The overall results are quite disappointing. Only a minority of patients achieved high-level, durable suppression with the follow-up regimen. One problem with the study is that relatively fewer ritonavir-boosted regimens were used in both the initial regimen and the follow-up regimen, so the results really reflect a past era of the use of PIs. My experience with agents such as lopinavir/ritonavir (LPV/r, Kaletra) is that failure rates with PI resistance are low, and that use of lopinavir/ritonavir after initial failure of a non-boosted PI is generally successful when resistance tests guide use of the entire regimen.
The authors screened 154 studies and then collectively analyzed results from 12 studies (7 clinical trials and 5 observational cohorts involving 1,197 patients) that met the predetermined definition of providing follow-up data for at least 24 weeks for the salvage regimen. An intent-to-treat form of meta-analysis was used, with the primary endpoint being the number of subjects with HIV RNA <500 copies/mL at 24 weeks.
Follow-up regimen types were characterized into 4 categories: (1) no new drug classes used, (2) boosted PI regimen without addition of any new class, (3) addition of NNRTI in NNRTI-naive subjects, and (4) addition of NNRTI and boosted PI in subjects naive to both.
The overall rate of virologic suppression (<500 copies/mL) at 24 weeks was 38%. The lowest rate was seen in subjects with no new drug classes added (16%), compared with 27% for the boosted-PI group, 39% for the new-NNRTI group, and 54% for addition of both a first NNRTI and boosted PI.
Regression analysis of predictors of success at week 24 found that baseline HIV-RNA level and the rescue regimen type were significant, whereas baseline CD4+ cell count was not. The fact that the success rate was highest for the group adding a first NNRTI and boosted PI is not very relevant when the DHHS-recommended first ART regimens contain either efavirenz (EFV, Sustiva, Stocrin) or lopinavir/ritonavir.
I also have concerns about the durability of a regimen when adding only a new NNRTI in the setting of both PI and nucleoside reverse transcriptase inhibitor (NRTI) failure. Current practice in the United States is to evaluate the effectiveness of ART using a more sensitive assay (usually <50-75 copies/mL), which, if used in the studies reviewed here, would undoubtedly have decreased the success rate significantly.
The use of resistance tests to guide the choice of drugs within classes is also the community standard. It is therefore disappointing that many of the studies did not use this tool to help them select the regimen.
Also, why do so many current rescue studies designate a regimen that is often suboptimal and does not allow the full use of all available drugs and regimens? A major challenge is not only to develop new drugs that are active against resistant virus, but to design studies utilizing the best that current knowledge and resources can offer, so that more meaningful results can be obtained.
Exactly How Does the Immune System Fit Into the ART Equation?
With all of the understandable focus on the benefits of ART, the relevance of the immune system to the effectiveness, or lack thereof, of treatment remains an enigma. Many patients demonstrate a lack of CD4+ cell response, while others have an unexpectedly fabulous CD4+ cell response, though all have high-level HIV suppression. It is still unclear and often unpredictable why there is so much variation from patient to patient. This study from the Immunology Group of the ACTG sheds new light on this issue.
Mildvan D, Bosch RJ, Kim RS, et al. Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response. J Infect Dis. May 15, 2004;189(10):1811-1820.
The Immunophenotypic Markers and Antiretroviral Therapy (IMART) study used a novel data-sharing strategy involving data from 5 ACTG trials that measured naive and activated CD4 and CD8+ T cells in 324 subjects.
A regression model that adjusted for baseline CD4+ cell count, plasma HIV-RNA level and study demonstrated that high pretreatment CD8+ cell activation predicted subsequent virologic failure (P = .046). Another model revealed that the greatest increases in CD4+ cell counts were seen in subjects with the highest pretreatment-naive CD4+ cell counts, an effect that was magnified by high CD4+ cell and low CD8+ cell activation rates. The total lymphocyte count also predicted the subsequent change in CD4+ cell count.
The authors concluded that T-cell markers are predictive of treatment outcome, and may have merit in the study or management of HIV-1 infection.
A Possible Explanation of How GBV-C Infection Might Inhibit HIV Replication
In the April 2004 edition of The Body Pro's HIV JournalView, David Wohl highlighted several studies regarding the impact of GB virus C (GBV-C) on the natural history of HIV infection (the conclusion was that it has a seemingly positive impact). In this article, just published in The Lancet by Jack Stapleton and colleagues from the University of Iowa, the authors evaluated peripheral blood mononuclear cells (PBMCs) coinfected with GBV-C and HIV. The conclusion was that GBV-C induces inhibitory chemokines and downregulates CCR5 expression. As the Lancet editors note, that mechanism provides useful insight into potential new strategies for both anti-HIV medication and disease-modifying vaccine development.
Xiang J, George SL, Wünschmann S, Chang Q, Klinzman D, Stapleton JT. Inhibition of HIV-1 replication by GB virus C infection through increases in RANTES, MIP-1a, MIP-1B, and SDF-1. Lancet. June 19, 2004;363(9426):2040-2046.
Previously published data provided by the study authors have generally, but not universally, reported that persistent GBV-C infection slows the progression rate of HIV to AIDS. Though there were a variety of proposed mechanisms for that effect, there was little actual data.
In this study, the investigators coinfected PBMCs with GBV-C and HIV, then monitored infectivity and HIV p24 antigen production. GBV-C infection of PBMCs resulted in decreased replication of both clinical and laboratory strains of HIV. The degree of inhibition was related to the dose and timing of GBV-C infection: higher inhibition was seen with higher doses of GBV-C and with increased time between GBV-C and HIV infection. This inhibition was seen with both the CCR5- and CXCR4-tropic strains of HIV. Expression of mRNA for the chemokines RANTES, MIP-1a, MIP-1b and SDF-1, and secretion of those chemokines into the culture supernatant, were higher in the GBV-C-infected cells than in controls. PBMC surface expression of CCR5 was lower in the GBV-C-infected cells. Finally, the inhibitory effect of GBV-C infection on HIV infection was blocked by neutralizing antibodies against the respective chemokines.
These intriguing results provide a plausible explanation for the effect of GBV-C infection on HIV. The study needs to be repeated in additional trials and different laboratories but, if confirmed, should stimulate research into novel anti-HIV drug and vaccine strategies.
The debate around the effects of GBV-C on the natural history of HIV infection underscores how much we still need to learn about how factors other than the standard surrogate markers of HIV-RNA levels and CD4+ cell count -- such as human leukocyte antigen type, chemokine and receptor levels, drug-metabolizing genotypes and thymic restorative capacity -- influence the clinical course of HIV infection in patients, and how we can use this information in decision making.
Is HAART Less Effective Against HIV-2 Infection in the United States?
HIV-2 infection has been fairly limited to West Africa, with a small number of imported cases in the United States. Available data suggest that HIV-2 is less pathogenic than HIV-1. The natural history of HIV-2 infection appears to involve a longer period of clinical latency, though it can still result in AIDS. There is little published data on how well HIV-2-infected patients respond to standard HAART regimens.
This article is important for several reasons. First, it summarizes details for 10 HIV-2-infected persons in the United States, which is helpful for those of us that have not seen many cases of HIV-2 infection.
Information relating to diagnosis of HIV-2 infection, measurement of quantitative HIV-2 RNA levels (performed at the Harvard School of Public Health using an in-house method), CD4+ cell counts and clinical features is provided. Finally, details about the response to a range of fairly standard HAART regimens are provided.
Mullins C, Eisen G, Popper S, et al. Highly active antiretroviral therapy and viral response in HIV type 2 infection. Clin Infect Dis. June 15, 2004;38(12):1771-1779.
Chris Mullins and colleagues have provided a useful service by summarizing experience with 10 HIV-2-infected patients (7 from Cape Verde and 1 each from Guinea, Ivory Coast and Sierra Leone) who received HAART in the United States from 1994-2004. The approach to HAART for these HIV-2-infected patients mirrored that for HIV-1, with the major exception being that NNRTI-based regimens were not used (currently approved NNRTIs are generally not active against HIV-2).
Three subjects were asymptomatic. The CD4+ cell counts for asymptomatic subjects were higher than for those who were symptomatic (median levels 639 and 175 cells/mm3, respectively). Plasma HIV-2 RNA was also higher for the symptomatic than for the asymptomatic subjects (median levels 4.7 and 2.5 log copies/mL, respectively). All of the symptomatic subjects had low CD4+ cell counts and elevated viral loads.
Treatment responses in the 7 symptomatic subjects were generally disappointing. Three of the 7 subjects had increased CD4+ cell counts, but none had a greater than 2-log reduction in HIV-2 RNA. Four of the 7 did not improve clinically, with 2 of those subjects having problems with adherence.
Some of the treatment regimens for those 7 patients would be considered marginally acceptable by today's standards (i.e., they took triple NRTIs or stavudine [d4T, Zerit] plus didanosine [ddI, Videx] plus nelfinavir [NFV, Viracept]). No subjects received an initial boosted-PI regimen, and some had prior dual-NRTI therapy. No resistance information was provided.
Importantly, the HIV-2 diagnosis for 3 of these patients was made after an initial diagnosis of HIV-1, with additional tests ordered after laboratory tests or response to treatment seemed not to fit the usual pattern. The treatment response reported here is disappointing but understandable, since many of the patients had prior suboptimal therapy with a variety of regimens. As the authors point out, more data is needed, particularly using subjects who from the beginning were given potent boosted PI-based regimens. This article is a good reference for clinicians to use if they encounter an HIV-2-infected patient.
Use of Nelfinavir for HIV-1 Type C Infection
In the United States, most HIV-1 infections involve subtype B virus but, worldwide, HIV-1 subtype C is probably the most common infection. The majority of the data regarding the use of ART has come from resource-rich countries, and therefore involves subtype B infections. However, different HIV-1 subtypes possess distinct amino-acid sequences in their proteins, including the viral protease. This study looked at the use of nelfinavir in patients infected with HIV-1 subtype C.
Nelfinavir's most desirable characteristic is that it preserves other PI treatment options after virologic failure when the D30N PI mutation develops. Data on that issue,11 however, have been mostly restricted to patients with subtype B HIV-1. This study compares the genotypic and phenotypic replication capacity of HIV-1 isolates from nelfinavir-treated patients infected with subtype B or C HIV-1. The results demonstrate that use of nelfinavir in patients infected with HIV-1 subtype C results in broader cross-resistance to other PIs than has been the experience in those infected with subtype B.
Grossman Z, Paxinos EE, Averbuch D, et al. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrobial Agents Chemother. June 2004;48(6):2159-2165.
Jonathan Shapiro and colleagues from ViroLogic and the Sheba Medical Center in Israel reported on the virologic features of 159 subtype-C-infected and 65 subtype-B-infected patients failing nelfinavir as their first PI.
The characteristic D30N PI mutation was seen in only 7% of the subtype-C-infected patients, compared with 23% of the subtype-B-infected patients (P = .03). Significant differences were also found in the occurrences of M36I (98 vs. 36%), L63P (35 vs. 59%), A71V (3 vs. 32%), V77I (0 vs. 36%) and I93L (91 vs. 32%) (.0001<P<.05) between subtype C and B HIV isolates from these patients. The subtype C isolates with the D30N mutation showed a change in 50% inhibitory concentration (IC50) in susceptibility to nelfinavir only -- much less than the change seen in subtype B isolates with the D30N mutation -- while other mutations increased the IC50 values for all PIs.
The replication capacity of the subtype C virus was reduced relative to a subtype B reference virus (details were not provided in the paper). The ViroLogic database was reviewed for the replication capacity of subtype C virus with the D30N versus the L90M and/or other mutations. Both groups had a lower replication capacity compared to wild-type virus, but there were no obvious differences between the 2 groups (data not provided).
This study has numerous limitations, notably that samples were not from patients in any form of randomized study, and in addition, information about adherence or treatment response was not available.
There may be some demographic differences between the patient populations. Subtype C patients are more likely to be from Africa, with lower socioeconomic standing, which could influence treatment outcomes. Nonetheless, the results confirm other reports that HIV-1 subtype-C-infected patients failing treatment with nelfinavir generally have a different resistance pathway than subtype-B-infected patients and develop broader PI cross-resistance, possibly due to different baseline polymorphisms. Use of nelfinavir as the first PI in subtype-C-infected patients would be less likely to preserve other PI treatment options than has been the experience in subtype-B-infected patients.
The International AIDS Disaster: Which Route Will China Take?
Although not a research article, this report provides an excellent overview of the HIV/AIDS situation in China. This is the third collection of articles in Science magazine's series on HIV in Asia (the first, published Sep. 19, 2003, focused on Southeast Asia; the second, published Apr. 23, 2004, focused on India). As the most populous country in the world, with a booming economy, China seems to be at high risk for a disastrous problem, while simultaneously having the resources to blunt the impact, if it can gather the political will to do so.
Cohen J. HIV/AIDS in China: poised for takeoff? Science. June 4, 2004;304(5676):1430-1439.
The introduction begins with a description of the Premier of China, Wen Jiabao, shaking hands with Sun Fuli, an HIV-infected taxi driver from Shanxi Province, on Dec. 1, 2003 -- World AIDS Day. The story was widely carried throughout China, and seemed to send a powerful message of the Chinese government's intentions to get serious about the threat of HIV.
Increased spending on treatment and education, pilot needle exchange and methadone treatment programs, and roll-outs of limited antiretroviral drug treatment programs all indicate that China has become serious about dealing with the country's estimated 840,000 HIV-infected persons -- two-thirds of whom are intravenous drug users (IDUs) -- as well as ramping up prevention efforts.
Although there are still many problems, the Chinese HIV situation has improved considerably relative to several years before. The history of the AIDS epidemic in China has been divided into 3 phases. From 1985 to 1988, the country reported only 22 infections, so the disease was viewed as a foreign problem. The government stated that the disease could be kept in check, because of limited homosexual activity as well as a believed low rate of promiscuity. In addition, they barred foreigners with HIV from living in the country. However, in 1989, around 150 IDUs in Yunnan Province tested positive for HIV. This signaled the "spreading phase" of the epidemic.
Adding to this was the fact that during the early 1990s, many commercial firms pooled blood from paid donors and returned the blood cells to the donors while keeping the plasma for sale. That and a lack of clean needles and HIV testing standards led to an estimated 250,000 infections.
The current "expansion phase" of the epidemic includes spread of HIV from IDUs to their partners and children, and now the rise of infection in sex workers and gay men. Another explanation for the rapid rise in reported HIV cases is clearly the government's more accurate reporting and expanded testing opportunities.
There is still considerable concern about human rights issues for HIV-infected persons in China. In addition, another article12 in this series discusses the limited availability of antiretroviral drugs.
When I was in China in May 2004, numerous physicians expressed their frustration that their only medications were didanosine and stavudine, which provide only marginal benefit and lead to high rates of neuropathy and pancreatitis.
This series makes for worthwhile reading, with specific articles on efforts to educate IDUs, the story of HIV-infected plasma donors in Henan Province and efforts to develop vaccines customized for China.
Joint Problems With HIV Infection -- Yes and No
Although not part of last month's journal publications, this additional review may be of interest. From early in the epidemic, HIV has been reportedly associated with various rheumatologic disorders. However, the diagnostic possibilities can be numerous when confronted with an HIV-infected patient with joint complaints. I often refer such patients to a rheumatologist to help sort out the likely cause and best approach to therapy. After one such referral of an HIV-infected, African-born patient, the rheumatologist sent the following 2 articles to help me beef up on the topic.
Solinger AM. Rheumatic manifestations of human immunodeficiency virus. Curr Rheumatol Rep. June 2003;5(3):205-209.
Various rheumatic, musculoskeletal or other immune disorders are associated with HIV infection. Reactive arthritis, psoriatic arthritis, acute nonspecific arthritis, Sjögren syndrome and inflammatory myositis have been reported. During the early years of the AIDS epidemic, there were numerous reports of "acute painful joints," which seem to have diminished. This review of the literature concludes that the possible association between HIV and rheumatic or definable autoimmune disorders is fairly limited to the reactive arthritidies. Vasculitis has more recently been associated with hepatitis C coinfection.
There actually seems to be a decreasing frequency of rheumatoid arthritis in the setting of HIV infection, with a worsening of pre-existing rheumatoid arthritis after the initiation of potent ART (possibly supporting the role of CD4+ cells in inflammatory synovitis). There also seems to be an increased incidence, though solid epidemiological evidence is sparse, of secondary muscle and joint infections in HIV patients.
Centers for Disease Control and Prevention. Primary and secondary syphilis -- United States, 2002. MMWR. November 21, 2003;52(46):1117-1120.
Centers for Disease Control and Prevention. Increases in HIV diagnosis -- 29 states, 1999-2002. MMWR. November 28, 2003;52(47):1145-1148.
Chakraborty H, Sen PK, Helms RW, et al. Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model. AIDS. March 30, 2001;15(5):621-627.
Bozzette SA, Berry SH, Duan N, et al. The care of HIV-infected adults in the United States. N Engl J Med. December 24, 1998;339(26):1897-1904.
Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA. July 14, 2004;292(2):251-265.
Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. July 4, 2000;133(1):21-30.
Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing "DOTS-plus". Br Med J. September 5, 1998;317(7159):671-674.
Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. January 9, 2003;348(2):119-128.
Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. N Engl J Med. January 18, 2001;344(3):159-167.
Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. October 3, 2000;133(7):493-503.
Clotet B, Ruiz L, Martinez-Picado J, Negredo E, Hill A, Popescu M. Prevalence of HIV protease mutations on failure of nelfinavir-containing HAART: a retrospective analysis of four clinical studies and two observational cohorts. HIV Clin Trials. July-August 2002;3(4):316-323.
Cohen J. HIV/AIDS in China: a new treatment campaign, but with limited weapons. Science. June 4, 2004;304(5676):1433-1434.